Benzene sulfonamide thiazole and oxazole compounds

ABSTRACT

The present invention provides thiazole sulfonamide and oxazole sulfonamide compounds, compositions containing the same, as well as processes for the preparation and methods for their use as pharmaceutical agents.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is filed as a continuation of application U.S. Ser. No.13/755,466, filed on Jan. 31, 2013 which is a continuation applicationof U.S. Ser. No. 12/991,004, filed Nov. 4, 2010 which issued as U.S.Pat. No. 8,415,345 on Apr. 9, 2013 which is a National Phase Applicationof International Patent Application Serial No. PCT/US2009/42682 filed onMay 4, 2009, which claims priority from 61/050,744 filed on May 6, 2008in the United States.

FIELD OF THE INVENTION

The present invention relates to benzene sulfonamide thiazole andoxazole compounds, compositions containing the same, as well asprocesses for the preparation and methods of using such compounds andcompositions.

BACKGROUND OF THE INVENTION

Both receptor tyrosine kinases and serine/threonine kinases have beenimplicated in cellular signaling pathways that control cell function,division, growth, differentiation, and death (apoptosis) throughreversible phosphorylation of the hydroxyl groups of tyrosine or serineand threonine residues, respectively, in proteins. In signaltransduction, for example, extracellular signals are transduced viamembrane receptor activation, with amplification and propagation using acomplex choreography of cascades of protein phosphorylation, and proteindephosphorylation events to avoid uncontrolled signaling. Thesesignaling pathways are highly regulated, often by complex andintermeshed kinase pathways where each kinase may itself be regulated byone or more other kinases and protein phosphatases. The biologicalimportance of these finely tuned systems is such that a variety of cellproliferative disorders have been linked to defects in one or more ofthe various cell signaling pathways mediated by tyrosine orserine/threonine kinases.

Receptor tyrosine kinases (RTKs) catalyze phosphorylation of certaintyrosyl amino acid residues in various proteins, including themselves,which govern cell growth, proliferation and differentiation.

Downstream of the several RTKs lie several signaling pathways, amongthem is the Ras-Raf-MEK-ERK kinase pathway. It is currently understoodthat activation of Ras GTPase proteins in response to growth factors,hormones, cytokines, etc. stimulates phosphorylation and activation ofRaf kinases. These kinases then phosphorylate and activate theintracellular protein kinases MEK1 and MEK2, which in turn phosphorylateand activate other protein kinases, ERK1 and 2. This signaling pathway,also known as the mitogen-activated protein kinase (MAPK) pathway orcytoplasmic cascade, mediates cellular responses to growth signals. Theultimate function of this is to link receptor activity at the cellmembrane with modification of cytoplasmic or nuclear targets that governcell proliferation, differentiation, and survival. Mutations in variousRas GTPases and the B-Raf kinase have been identified that can lead tosustained and constitutive activation of the MAPK pathway, ultimatelyresulting in increased cell division and survival. As a consequence ofthis, these mutations have been strongly linked with the establishment,development, and progression of a wide range of human cancers. Thebiological role of the Raf kinases, and specifically that of B-Raf, insignal transduction is described in Davies, H., et al., Nature (2002)9:1-6; Garnett, M. J. & Marais, R., Cancer Cell (2004) 6:313-319;Zebisch, A. & Troppmair, J., Cell. Mol. Life Sci. (2006) 63:1314-1330;Midgley, R. S. & Kerr, D. J., Crit. Rev. One/Hematol. (2002) 44:109-120;Smith, R. A., et al., Curr. Top. Med. Chem. (2006) 6:1071-1089; andDownward, J., Nat. Rev. Cancer (2003) 3:11-22.

Naturally occurring mutations of the B-Raf kinase that activate MAPKpathway signaling have been found in a large percentage of humanmelanomas (Davies (2002) supra) and thyroid cancers (Cohen et al J. Nat.Cancer Inst. (2003) 95(8) 625-627 and Kimura et al Cancer Res. (2003)63(7) 1454-1457), as well as at lower, but still significant,frequencies in the following:

-   Barret's adenocarcinoma (Garnett et al., Cancer Cell (2004) δ    313-319 and Sommerer et al Oncogene (2004) 23(2) 554-558),-   billiary tract carcinomas (Zebisch et al., Cell. Mol. Life    Sci. (2006) 63 1314-1330),-   breast cancer (Davies (2002) supra),-   cervical cancer (Moreno-Bueno et al Clin. Cancer Res. (2006) 12(12)    3865-3866),-   cholangiocarcinoma (Tannapfel et al Gut (2003) 52(5) 706-712),-   central nervous system tumors including primary CNS tumors such as    glioblastomas, astrocytomas and ependymomas (Knobbe et al Acta    Neuropathol. (Berl.) (2004) 108(6) 467-470, Davies (2002) supra, and    Garnett et al., Cancer Cell (2004) supra) and secondary CNS tumors    (i.e., metastases to the central nervous system of tumors    originating outside of the central nervous system),-   colorectal cancer, including large intestinal colon carcinoma (Yuen    et al Cancer Res. (2002) 62(22) 6451-6455, Davies (2002) supra and    Zebisch et al., Cell. Mol. Life Sci. (2006),-   gastric cancer (Lee et al Oncogene (2003) 22(44) 6942-6945),-   carcinoma of the head and neck including squamous cell carcinoma of    the head and neck (Cohen et al J. Nat. Cancer Inst. (2003) 95(8)    625-627 and Weber et al Oncogene (2003) 22(30) 4757-4759),-   hematologic cancers including leukemias (Garnett et al., Cancer    Cell (2004) supra, particularly acute lymphoblastic leukemia    (Garnett et al., Cancer Cell (2004) supra and Gustafsson et al    Leukemia (2005) 19(2) 310-312), acute myelogenous leukemia (AML)    (Lee et al Leukemia (2004) 18(1) 170-172, and Christiansen et al    Leukemia (2005) 19(12) 2232-2240), myelodysplastic syndromes    (Christiansen et al Leukemia (2005) supra) and chronic myelogenous    leukemia (Mizuchi et al Biochem. Biophys. Res. Commun. (2005) 326(3)    645-651); Hodgkin's lymphoma (Figl et al Arch. Dermatol. (2007)    143(4) 495-499), non-Hodgkin's lymphoma (Lee et al Br. J.    Cancer (2003) 89(10) 1958-1960), megakaryoblastic leukemia (Eychene    et al Oncogene (1995) 10(6) 1159-1165) and multiple myeloma (Ng et    al Br. J. Haematol. (2003) 123(4) 637-645),-   hepatocellular carcinoma (Garnett et al., Cancer Cell (2004),-   lung cancer (Brose et al Cancer Res. (2002) 62(23) 6997-7000, Cohen    et al J. Nat. Cancer Inst. (2003) supra and Davies (2002) supra),    including small cell lung cancer (Pardo et al EMBO J. (2006) 25(13)    3078-3088) and non-small cell lung cancer (Davies (2002) supra),-   ovarian cancer (Russell & McCluggage J. Pathol. (2004) 203(2)    617-619 and Davies (2002) supr), endometrial cancer (Garnett et al.,    Cancer Cell (2004) supra, and Moreno-Bueno et al Clin. Cancer    Res. (2006) supra),-   pancreatic cancer (Ishimura et al Cancer Lett. (2003) 199(2)    169-173),-   pituitary adenoma (De Martino et al J. Endocrinol. Invest. (2007)    30(1) RC1-3),-   prostate cancer (Cho et al Int. J. Cancer (2006) 119(8) 1858-1862),-   renal cancer (Nagy et al Int. J. Cancer (2003) 106(6) 980-981),-   sarcoma (Davies (2002) supra), and-   skin cancers (Rodriguez-Viciana et al Science (2006) 311(5765)    1287-1290 and Davies (2002) supra).

Overexpression of c-Raf has been linked to AML (Zebisch et al., CancerRes. (2006) 66(7) 3401-3408, and Zebisch (Cell. Mol. Life Sci. (2006))and erythroleukemia (Zebisch et al., Cell. Mol. Life Sci. (2006).

By virtue of the role played by the Raf family kinases in these cancersand exploratory studies with a range of preclinical and therapeuticagents, including one selectively targeted to inhibition of B-Raf kinaseactivity (King A. J., et al., (2006) Cancer Res. 66:11100-11105), it isgenerally accepted that inhibitors of one or more Raf family kinaseswill be useful for the treatment of such cancers or other conditionassociated with Raf kinase.

Mutation of B-Raf has also been implicated in other conditions,including cardio-facio cutaneous syndrome (Rodriguez-Viciana et alScience (2006) 311(5765) 1287-1290) and polycystic kidney disease (Nagaoet al Kidney Int. (2003) 63(2) 427-437).

SUMMARY OF THE INVENTION

In a first aspect of the present invention, there is provided compoundsof formula (I):

wherein:

-   a is 0, 1, 2 or 3;-   each R¹ is the same or different and is independently selected from    halo, alkyl, haloalkyl, —OR⁶, —CO₂R⁶, —NR⁶R⁷, and —CN;-   Ring A is selected from C₃₋₆cycloalkyl, phenyl, 5-6 membered    heterocycle and 5-6 membered heteroaryl, said heterocycle and said    heteroaryl each having 1 or 2 heteroatoms selected from N, O and S;-   each of Q¹, Q², Q³ and Q⁴ is CH, C—R² or N, wherein not more than    one of Q¹, Q², Q³, and Q⁴ is N;-   each R² is the same or different and is independently selected from    halo, alkyl, haloalkyl, and —OR⁶;-   W is selected from —O— and —S—;-   R³ is selected from H, alkyl, haloalkyl-, -alkylene-OH, —NR⁶R⁷,    —C₃₋₆cycloalkyl, -alkylene-C(O)—OH, -alkylene-NH₂, and Het;    -   wherein said R³ C₃₋₆cycloalkyl is optionally substituted with 1        or 2 substituents which are the same or different and are        independently selected from halo, C₁₋₃alkyl, haloC₁₋₃alkyl, OH,        O—C₁₋₃alkyl, oxo, S(C₁₋₃alkyl), SO₂, NH₂, N(H)C₁₋₃alkyl and        N(C₁₋₃alkyl)₂;    -   Het is a 5-6 membered heterocycle having 1 or 2 heteroatoms        selected from N, O and S and optionally substituted with 1 or 2        substituents which are the same or different and are each        independently selected from halo, C₁₋₃alkyl, haloC₁₋₃alkyl,        O—C₁₋₃alkyl, C₁₋₃alkylene-O—C₁₋₃alkyl, OH, C₁₋₃alkylene-OH, oxo,        SO₂(C₁₋₃alkyl), C₁₋₃alkylene-SO₂(C₁₋₃alkyl), NH₂, N(H)C₁₋₃alkyl,        N(C₁₋₃alkyl)₂, CN, and —CH₂CN;        R⁴ is selected from H, alkyl, haloalkyl, alkenyl, —OR⁶, —R⁵—OR⁶,        —R⁵—CO₂R⁶, —R⁵—SO₂R⁶, —R⁵-Het, —R⁵—C(O)-Het, —N(H)R⁸, —N(CH₃)R⁸,        and —R⁵—NR⁶R⁷; each R⁵ is the same or different and is        independently C₁₋₄alkylene;        each R⁶ and each R⁷ is the same or different and is        independently selected from H, alkyl, haloalkyl, —C(O)-alkyl,        and —C(O)-cycloalkyl;-   R⁸ is selected from H, alkyl (optionally substituted by —OH),    haloalkyl, C₃₋₆cycloalkyl, —R⁵—C₃₋₆cycloalkyl, Het², —R⁵-Het²,    —R⁵—OR⁶, —R⁵—O—R⁵—OR⁶, —R⁵—C(O)₂R⁶, —R⁵—C(O)NR⁶R⁷, —R⁵—N(H)C(O)—R⁶,    —R⁵—N(H)C(O)—R⁵—OR⁶, —R⁵—N(H)C(O)₂—R⁶, —R⁵—NR⁶R⁷, —R⁵—S(O)₂R⁶,    —R⁵—CN, and —R⁵—N(H)S(O)₂R⁶;    -   wherein said R⁸ C₃₋₆cycloalkyl is optionally substituted with 1        or 2 substituents which are the same or different and are        independently selected from halo, C₁₋₃alkyl, haloC₁₋₃alkyl, OH,        O—C₁₋₃alkyl, oxo, S(C₁₋₃alkyl), SO₂(C₁₋₃alkyl), NH₂,        N(H)C₁₋₃alkyl and N(C₁₋₃alkyl)₂, and N(H)SO₂C₁₋₃alkyl; and    -   Het² is a 4-6 membered heterocycle having 1 or 2 heteroatoms        selected from N, O and S and optionally substituted with 1, 2,        3, 4 or 5 C₁₋₃alkyl or 1 or 2 substituents which are the same or        different and are each independently selected from halo,        C₁₋₃alkyl, haloC₁₋₃alkyl, O—C₁₋₃alkyl, C₁₋₃alkylene-O—C₁₋₃alkyl,        OH, C₁₋₃alkylene-OH, oxo, SO₂(C₁₋₃alkyl),        C₁₋₃alkylene-SO₂(C₁₋₃alkyl), NH₂, N(H)C₁₋₃alkyl, N(C₁₋₃alkyl)₂,        N(H)SO₂C₁₋₃alkyl, C(O)(C₁₋₃alkyl), CO₂(C₁₋₄alkyl), CN, and        —CH₂CN;        and R⁹ and R¹⁹ are independently selected from H and alkyl,        and pharmaceutically acceptable salts thereof.

In a second aspect of the present invention, there is provided compoundsof formula (I-i)

wherein Q⁴ is CH or C—R² and all other variables are as defined above,and pharmaceutically acceptable salts thereof.

In a third aspect of the present invention, there is provided compoundsof formula (I-i-b)

wherein all variables are as defined above, and pharmaceuticallyacceptable salts thereof.

In a fourth aspect of the present invention, there is provided compoundsof formula (I-iii-a)

wherein Q⁴ is CH or C—R² and all other variables are as defined above,and pharmaceutically acceptable salts thereof.

In a fifth aspect of the present invention, there is provided compoundsof formula (I-iii-b)

wherein Q⁴ is CH or C—R² and all other variables are as defined above,and pharmaceutically acceptable salts thereof.

In a sixth aspect of the present invention, there is provided compoundsof formula (I-iv):

wherein Q⁴ is CH or C—R² and all other variables are as defined above,and pharmaceutically acceptable salts thereof.

In a seventh aspect of the present invention, there is providedcompounds of formula (I-v):

wherein Q⁴ is CH or C—R² and all other variables are as defined above,and pharmaceutically acceptable salts thereof.

In an eighth aspect of the present invention, there is providedcompounds of formula (I-vii):

wherein Q⁴ is CH or C—R², and all variables are as defined above, andpharmaceutically acceptable salts thereof.

In a ninth aspect of the present invention, there is provided a compoundselected from:

and pharmaceutically acceptable salts thereof.

And more particularly, there is provided a compound selected from:

and pharmaceutically acceptable salts thereof.

In a tenth aspect of the present invention, there is provided a compoundselected from

-   N-{3-[5-(2-amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide;-   N-{3-[2-(1,1-dimethylethyl)-5-(2-methyl-4-pyrimidinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide;-   N-{3-[5-(2-amino-4-pyrimidinyl)-2-(tetrahydro-2H-pyran-4-yl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide;-   N-{3-[5-(2-amino-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide;-   N-{3-[5-(2-amino-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]-2-chlorophenyl}-2-furansulfonamide;-   N-{3-[5-(2-amino-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]-2-chlorophenyl}-2,5-difluorobenzenesulfonamide;    and-   N-{3-[2-(1,1-dimethylethyl)-5-(4-pyrimidinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide.

In another aspect of the present invention there is providedN-{3-[5-(2-amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide

and pharmaceutically acceptable salts thereof. Particularly the freebase of the compound.

In another aspect of the present invention there is providedN-{3-[2-(1,1-dimethylethyl)-5-(2-methyl-4-pyrimidinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide

and pharmaceutically acceptable salts thereof. Particularly the freebase of the compound.

In another aspect of the present invention there is providedN-{3-[5-(2-amino-4-pyrimidinyl)-2-(tetrahydro-2H-pyran-4-yl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide

and pharmaceutically acceptable salts thereof. Particularly the freebase of the compound.

In another aspect of the present invention there is providedN-{3-[5-(2-amino-4-pyrimidinyl)-2-(tetrahydro-2H-pyran-4-yl)-1,3-thiazol-4-yl]-2-chlorophenyl}-3-furansulfonamide

and pharmaceutically acceptable salts thereof. Particularly the freebase of the compound.

In another aspect of the present invention there is providedN-{3-[5-(2-amino-4-pyrimidinyl)-2-(tetrahydro-2H-pyran-4-yl)-1,3-thiazol-4-yl]-2-fluorophenyl}-3-furansulfonamide

and pharmaceutically acceptable salts thereof. Particularly the freebase of the compound.

In another aspect of the present invention, there is provided apharmaceutical composition comprising a compound of formula (I)(including any particular sub-generic formula described herein) or apharmaceutically acceptable salt thereof. In one embodiment, thepharmaceutical composition further comprises one or more ofpharmaceutically acceptable carriers, diluents or excipients. In oneaspect, the present invention provides a pharmaceutical compositioncomprising any of

-   N-{3-[5-(2-amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide;-   N-{3-[2-(1,1-dimethylethyl)-5-(2-methyl-4-pyrimidinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide;    or-   N-{3-[5-(2-amino-4-pyrimidinyl)-2-(tetrahydro-2H-pyran-4-yl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide    or a pharmaceutically acceptable salt thereof. Particularly the free    base of any of the foregoing compounds.

In another aspect of the present invention, there is provided a methodof treating a susceptible neoplasm in a mammal in need thereof,comprising administering to the mammal a therapeutically effectiveamount of a compound of formula (I) (including any particularsub-generic formula described herein) or a pharmaceutically acceptablesalt thereof. Susceptible neoplasms include e.g., Barret'sadenocarcinoma; billiary tract carcinomas; breast cancer; cervicalcancer; cholangiocarcinoma; central nervous system tumors includingprimary CNS tumors such as glioblastomas, astrocytomas (e.g.,glioblastoma multiforme) and ependymomas, and secondary CNS tumors(i.e., metastases to the central nervous system of tumors originatingoutside of the central nervous system); colorectal cancer includinglarge intestinal colon carcinoma; gastric cancer; carcinoma of the headand neck including squamous cell carcinoma of the head and neck;hematologic cancers including leukemias and lymphomas such as acutelymphoblastic leukemia, acute myelogenous leukemia (AML),myelodysplastic syndromes, chronic myelogenous leukemia, Hodgkin'slymphoma, non-Hodgkin's lymphoma, megakaryoblastic leukemia, multiplemyeloma and erythroleukemia; hepatocellular carcinoma; lung cancerincluding small cell lung cancer and non-small cell lung cancer; ovariancancer; endometrial cancer; pancreatic cancer; pituitary adenoma;prostate cancer; renal cancer; sarcoma; skin cancers includingmelanomas; and thyroid cancers.

In another aspect of the present invention, there is provided a methodof treating breast cancer, cholangiocarcinoma, colorectal cancer,melanoma, non-small cell lung cancer, ovarian cancer, or thyroid cancer,in a mammal, particularly a human, in need thereof, comprisingadministering to the mammal (e.g. human) a therapeutically effectiveamount of a compound of formula (I) or a pharmaceutically acceptablesalt thereof.

In another aspect of the present invention, there is provided a methodof treating a susceptible neoplasm in a mammal, particularly a human, inneed thereof, comprising administering to the mammal (e.g. human) atherapeutically effective amount of a compound selected from

-   N-{3-[5-(2-amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide;-   N-{3-[2-(1,1-dimethylethyl)-5-(2-methyl-4-pyrimidinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide;-   N-{3-[5-(2-amino-4-pyrimidinyl)-2-(tetrahydro-2H-pyran-4-yl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide;-   N-{3-[5-(2-amino-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide;-   N-{3-[5-(2-amino-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]-2-chlorophenyl}-2-furansulfonamide;-   N-{3-[5-(2-amino-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]-2-chlorophenyl}-2,5-difluorobenzenesulfonamide;    and-   N-{3-[2-(1,1-dimethylethyl)-5-(4-pyrimidinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide;-   N-{3-[5-(2-amino-4-pyrimidinyl)-2-(tetrahydro-2H-pyran-4-yl)-1,3-thiazol-4-yl]-2-chlorophenyl}-3-furansulfonamide;-   N-{3-[5-(2-amino-4-pyrimidinyl)-2-(tetrahydro-2H-pyran-4-yl)-1,3-thiazol-4-yl]-2-fluorophenyl}-3-furansulfonamide,    and pharmaceutically acceptable salts thereof,    and particularly selected from-   N-{3-[5-(2-amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide;-   N-{3-[2-(1,1-dimethylethyl)-5-(2-methyl-4-pyrimidinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide;-   N-{3-[5-(2-amino-4-pyrimidinyl)-2-(tetrahydro-2H-pyran-4-yl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide;-   N-{3-[5-(2-amino-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide;-   N-{3-[5-(2-amino-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]-2-chlorophenyl}-2-furansulfonamide;-   N-{3-[5-(2-amino-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]-2-chlorophenyl}-2,5-difluorobenzenesulfonamide;    and-   N-{3-[2-(1,1-dimethylethyl)-5-(4-pyrimidinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide;    and    pharmaceutically acceptable salts thereof. Particularly the free    base of any of the compounds.

In another aspect of the present invention, there is provided a methodof treating breast cancer, cholangiocarcinoma, colorectal cancer,melanoma, non-small cell lung cancer, ovarian cancer, or thyroid cancer,in a mammal, particularly a human, in need thereof, comprisingadministering to the mammal (e.g. human) a therapeutically effectiveamount of

-   N-{3-[5-(2-amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide;-   N-{3-[2-(1,1-dimethylethyl)-5-(2-methyl-4-pyrimidinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide;    or-   N-{3-[5-(2-amino-4-pyrimidinyl)-2-(tetrahydro-2H-pyran-4-yl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide;    or a pharmaceutically acceptable salt thereof. Particularly the free    base of any of the compounds.

In another aspect, there is provided a method for treatingcholangiocarcinoma, colorectal cancer, melanoma or thyroid cancer in ahuman in need thereof, comprising administering to the human, atherapeutically effective amount of

-   N-{3-[5-(2-amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide;-   N-{3-[2-(1,1-dimethylethyl)-5-(2-methyl-4-pyrimidinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide;    or-   N-{3-[5-(2-amino-4-pyrimidinyl)-2-(tetrahydro-2H-pyran-4-yl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide;    or a pharmaceutically acceptable salt thereof. Particularly the free    base of any of the compounds.

In another aspect of the present invention, there is provided a processfor preparing a compound of formula (I) or a pharmaceutically acceptablesalt thereof. The process comprises reacting a compound of formula(VIII):

-   -   wherein R¹⁰ is halo or thiomethyl;        with one of:    -   i) molecular hydrogen, or    -   ii) an alkyl metal reagent or alkenyl metal reagent, or    -   iii) an alcohol, or    -   iv) a compound of formula (IX): N(R^(a))—R⁸, wherein R^(a) is H        or CH₃ and R⁸ is as defined above;        to prepare a compound of formula (I).

In another aspect of the present invention, there is provided a processfor preparing a compound of formula (I) or a pharmaceutically acceptablesalt thereof. The process comprises reacting a compound of formula(XVIII):

with a compound of formula (VII):

In another aspect of the present invention, there is provided a compoundof formula (I), (including any particular sub-generic formula describedherein) or a pharmaceutically acceptable salt thereof for use intherapy.

In another aspect, there is provided a compound of formula (I)(including any particular sub-generic formula described herein) or apharmaceutically acceptable salt thereof for use in the treatment of asusceptible neoplasm (e.g., Barret's adenocarcinoma; billiary tractcarcinomas; breast cancer; cervical cancer; cholangiocarcinoma; centralnervous system tumors including primary CNS tumors such asglioblastomas, astrocytomas (e.g., glioblastoma multiforme) andependymomas, and secondary CNS tumors (i.e., metastases to the centralnervous system of tumors originating outside of the central nervoussystem); colorectal cancer including large intestinal colon carcinoma;gastric cancer; carcinoma of the head and neck including squamous cellcarcinoma of the head and neck; hematologic cancers including leukemiasand lymphomas such as acute lymphoblastic leukemia, acute myelogenousleukemia (AML), myelodysplastic syndromes, chronic myelogenous leukemia,Hodgkin's lymphoma, non-Hodgkin's lymphoma, megakaryoblastic leukemia,multiple myeloma and erythroleukemia; hepatocellular carcinoma; lungcancer including small cell lung cancer and non-small cell lung cancer;ovarian cancer; endometrial cancer; pancreatic cancer; pituitaryadenoma; prostate cancer; renal cancer; sarcoma; skin cancers includingmelanomas; and thyroid cancers) in a mammal (e.g., human) in needthereof.

In another aspect, there is provided a compound of formula (I)(including any particular sub-generic formula described herein) or apharmaceutically acceptable salt thereof for use in the treatment ofbreast cancer, cholangiocarcinoma, colorectal cancer, melanoma,non-small cell lung cancer, ovarian cancer, or thyroid cancer in amammal (e.g., human) in need thereof.

In another aspect, there is provided a compound selected from

-   N-{3-[5-(2-amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide;-   N-{3-[2-(1,1-dimethylethyl)-5-(2-methyl-4-pyrimidinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide;-   N-{3-[5-(2-amino-4-pyrimidinyl)-2-(tetrahydro-2H-pyran-4-yl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide;-   N-{3-[5-(2-amino-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide;-   N-{3-[5-(2-amino-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]-2-chlorophenyl}-2-furansulfonamide;-   N-{3-[5-(2-amino-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]-2-chlorophenyl}-2,5-difluorobenzenesulfonamide;    and-   N-{3-[2-(1,1-dimethylethyl)-5-(4-pyrimidinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide;-   N-{3-[5-(2-amino-4-pyrimidinyl)-2-(tetrahydro-2H-pyran-4-yl)-1,3-thiazol-4-yl]-2-chlorophenyl}-3-furansulfonamide;-   N-{3-[5-(2-amino-4-pyrimidinyl)-2-(tetrahydro-2H-pyran-4-yl)-1,3-thiazol-4-yl]-2-fluorophenyl}-3-furansulfonamide;    and    pharmaceutically acceptable salts thereof (particularly the free    base forms) for use in the treatment of a susceptible neoplasm    (e.g., Barret's adenocarcinoma; billiary tract carcinomas; breast    cancer; cervical cancer; cholangiocarcinoma; central nervous system    tumors including primary CNS tumors such as glioblastomas,    astrocytomas (e.g., glioblastoma multiforme) and ependymomas, and    secondary CNS tumors (i.e., metastases to the central nervous system    of tumors originating outside of the central nervous system);    colorectal cancer including large intestinal colon carcinoma;    gastric cancer; carcinoma of the head and neck including squamous    cell carcinoma of the head and neck; hematologic cancers including    leukemias and lymphomas such as acute lymphoblastic leukemia, acute    myelogenous leukemia (AML), myelodysplastic syndromes, chronic    myelogenous leukemia, Hodgkin's lymphoma, non-Hodgkin's lymphoma,    megakaryoblastic leukemia, multiple myeloma and erythroleukemia;    hepatocellular carcinoma; lung cancer including small cell lung    cancer and non-small cell lung cancer; ovarian cancer; endometrial    cancer; pancreatic cancer; pituitary adenoma; prostate cancer; renal    cancer; sarcoma; skin cancers including melanomas; and thyroid    cancers) in a mammal (e.g., human) in need thereof.

In another aspect, there is provided

-   N-{3-[5-(2-amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide;-   N-{3-[2-(1,1-dimethylethyl)-5-(2-methyl-4-pyrimidinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide;-   N-{3-[5-(2-amino-4-pyrimidinyl)-2-(tetrahydro-2H-pyran-4-yl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide;-   N-{3-[5-(2-amino-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide;-   N-{3-[5-(2-amino-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]-2-chlorophenyl}-2-furansulfonamide;-   N-{3-[5-(2-amino-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]-2-chlorophenyl}-2,5-difluorobenzenesulfonamide;    or-   N-{3-[2-(1,1-dimethylethyl)-5-(4-pyrimidinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide;-   N-{3-[5-(2-amino-4-pyrimidinyl)-2-(tetrahydro-2H-pyran-4-yl)-1,3-thiazol-4-yl]-2-chlorophenyl}-3-furansulfonamide;-   N-{3-[5-(2-amino-4-pyrimidinyl)-2-(tetrahydro-2H-pyran-4-yl)-1,3-thiazol-4-yl]-2-fluorophenyl}-3-furansulfonamide;    or a pharmaceutically acceptable salt thereof (particularly the free    base of any of the compounds) for use in the treatment of breast    cancer, cholangiocarcinoma, colorectal cancer, melanoma, non-small    cell lung cancer, ovarian cancer, or thyroid cancer in a mammal    (e.g., human) in need thereof.

In a another aspect of the present invention, there is provided the useof a compound of formula (I) (including any particular sub-genericformula described herein) or a pharmaceutically acceptable salt thereof,in the preparation of a medicament for use in the treatment of asusceptible neoplasm (e.g., Barret's adenocarcinoma; billiary tractcarcinomas; breast cancer; cervical cancer; cholangiocarcinoma; centralnervous system tumors including primary CNS tumors such asglioblastomas, astrocytomas (e.g., glioblastoma multiforme) andependymomas, and secondary CNS tumors (i.e., metastases to the centralnervous system of tumors originating outside of the central nervoussystem); colorectal cancer including large intestinal colon carcinoma;gastric cancer; carcinoma of the head and neck including squamous cellcarcinoma of the head and neck; hematologic cancers including leukemiasand lymphomas such as acute lymphoblastic leukemia, acute myelogenousleukemia (AML), myelodysplastic syndromes, chronic myelogenous leukemia,Hodgkin's lymphoma, non-Hodgkin's lymphoma, megakaryoblastic leukemia,multiple myeloma and erythroleukemia; hepatocellular carcinoma; lungcancer including small cell lung cancer and non-small cell lung cancer;ovarian cancer; endometrial cancer; pancreatic cancer; pituitaryadenoma; prostate cancer; renal cancer; sarcoma; skin cancers includingmelanomas; and thyroid cancers) in a mammal (e.g., human) in needthereof.

In a another aspect of the present invention, there is provided the useof a compound of formula (I) (including any particular sub-genericformula described herein) or a pharmaceutically acceptable salt thereof,in the preparation of a medicament for use in the treatment of breastcancer, cholangiocarcinoma, colorectal cancer, melanoma, non-small celllung cancer, ovarian cancer, or thyroid cancer in a mammal (e.g., human)in need thereof.

In a another aspect of the present invention, there is provided the useof a compound selected from

-   N-{3-[5-(2-amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide;-   N-{3-[2-(1,1-dimethylethyl)-5-(2-methyl-4-pyrimidinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide;-   N-{3-[5-(2-amino-4-pyrimidinyl)-2-(tetrahydro-2H-pyran-4-yl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide;-   N-{3-[5-(2-amino-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide;-   N-{3-[5-(2-amino-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]-2-chlorophenyl}-2-furansulfonamide;-   N-{3-[5-(2-amino-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]-2-chlorophenyl}-2,5-difluorobenzenesulfonamide;    and-   N-{3-[2-(1,1-dimethylethyl)-5-(4-pyrimidinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide;-   N-{3-[5-(2-amino-4-pyrimidinyl)-2-(tetrahydro-2H-pyran-4-yl)-1,3-thiazol-4-yl]-2-chlorophenyl}-3-furansulfonamide;-   N-{3-[5-(2-amino-4-pyrimidinyl)-2-(tetrahydro-2H-pyran-4-yl)-1,3-thiazol-4-yl]-2-fluorophenyl}-3-furansulfonamide;    and    pharmaceutically acceptable salts thereof (particularly the free    base forms) for the preparation of a medicament for the treatment of    a susceptible neoplasm (e.g., Barret's adenocarcinoma; billiary    tract carcinomas; breast cancer; cervical cancer;    cholangiocarcinoma; central nervous system tumors including primary    CNS tumors such as glioblastomas, astrocytomas (e.g., glioblastoma    multiforme) and ependymomas, and secondary CNS tumors (i.e.,    metastases to the central nervous system of tumors originating    outside of the central nervous system); colorectal cancer including    large intestinal colon carcinoma; gastric cancer; carcinoma of the    head and neck including squamous cell carcinoma of the head and    neck; hematologic cancers including leukemias and lymphomas such as    acute lymphoblastic leukemia, acute myelogenous leukemia (AML),    myelodysplastic syndromes, chronic myelogenous leukemia, Hodgkin's    lymphoma, non-Hodgkin's lymphoma, megakaryoblastic leukemia,    multiple myeloma and erythroleukemia; hepatocellular carcinoma; lung    cancer including small cell lung cancer and non-small cell lung    cancer; ovarian cancer; endometrial cancer; pancreatic cancer;    pituitary adenoma; prostate cancer; renal cancer; sarcoma; skin    cancers including melanomas; and thyroid cancers) in a mammal (e.g.,    human) in need thereof.

In a another aspect of the present invention, there is provided the useof a compound selected from

-   N-{3-[5-(2-amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide;-   N-{3-[2-(1,1-dimethylethyl)-5-(2-methyl-4-pyrimidinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide;-   N-{3-[5-(2-amino-4-pyrimidinyl)-2-(tetrahydro-2H-pyran-4-yl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide;-   N-{3-[5-(2-amino-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide;-   N-{3-[5-(2-amino-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]-2-chlorophenyl}-2-furansulfonamide;-   N-{3-[5-(2-amino-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]-2-chlorophenyl}-2,5-difluorobenzenesulfonamide;-   N-{3-[2-(1,1-dimethylethyl)-5-(4-pyrimidinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide;-   N-{3-[5-(2-amino-4-pyrimidinyl)-2-(tetrahydro-2H-pyran-4-yl)-1,3-thiazol-4-yl]-2-chlorophenyl}-3-furansulfonamide;-   N-{3-[5-(2-amino-4-pyrimidinyl)-2-(tetrahydro-2H-pyran-4-yl)-1,3-thiazol-4-yl]-2-fluorophenyl}-3-furansulfonamide;    and    pharmaceutically acceptable salts thereof (particularly the free    base forms) for the preparation of a medicament for the treatment of    breast cancer, cholangiocarcinoma, colorectal cancer, melanoma,    non-small cell lung cancer, ovarian cancer, or thyroid cancer in a    mammal (e.g., human) in need thereof.

In another aspect of the present invention, there is provided apharmaceutical composition comprising a compound of formula (I)(including any particular sub-generic formula described herein) or apharmaceutically acceptable salt thereof for use in the treatment of asusceptible neoplasm (e.g., Barret's adenocarcinoma; billiary tractcarcinomas; breast cancer; cervical cancer; cholangiocarcinoma; centralnervous system tumors including primary CNS tumors such asglioblastomas, astrocytomas (e.g., glioblastoma multiforme) andependymomas, and secondary CNS tumors (i.e., metastases to the centralnervous system of tumors originating outside of the central nervoussystem); colorectal cancer including large intestinal colon carcinoma;gastric cancer; carcinoma of the head and neck including squamous cellcarcinoma of the head and neck; hematologic cancers including leukemiasand lymphomas such as acute lymphoblastic leukemia, acute myelogenousleukemia (AML), myelodysplastic syndromes, chronic myelogenous leukemia,Hodgkin's lymphoma, non-Hodgkin's lymphoma, megakaryoblastic leukemia,multiple myeloma and erythroleukemia; hepatocellular carcinoma; lungcancer including small cell lung cancer and non-small cell lung cancer;ovarian cancer; endometrial cancer; pancreatic cancer; pituitaryadenoma; prostate cancer; renal cancer; sarcoma; skin cancers includingmelanomas; and thyroid cancers) in a mammal (e.g., human) in needthereof.

In another aspect of the present invention, there is provided apharmaceutical composition comprising a compound of formula (I)(including any particular sub-generic formula described herein) or apharmaceutically acceptable salt thereof for use in the treatment ofbreast cancer, colorectal cancer, melanoma, non-small cell lung cancer,ovarian cancer, or thyroid cancer in a mammal (e.g., human) in needthereof.

In another aspect of the present invention, there is provided apharmaceutical composition comprising a compound selected from

-   N-{3-[5-(2-amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide;-   N-{3-[2-(1,1-dimethylethyl)-5-(2-methyl-4-pyrimidinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide;-   N-{3-[5-(2-amino-4-pyrimidinyl)-2-(tetrahydro-2H-pyran-4-yl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide;-   N-{3-[5-(2-amino-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide;-   N-{3-[5-(2-amino-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]-2-chlorophenyl}-2-furansulfonamide;-   N-{3-[5-(2-amino-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]-2-chlorophenyl}-2,5-difluorobenzenesulfonamide;-   N-{3-[2-(1,1-dimethylethyl)-5-(4-pyrimidinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide;-   N-{3-[5-(2-amino-4-pyrimidinyl)-2-(tetrahydro-2H-pyran-4-yl)-1,3-thiazol-4-yl]-2-chlorophenyl}-3-furansulfonamide;-   N-{3-[5-(2-amino-4-pyrimidinyl)-2-(tetrahydro-2H-pyran-4-yl)-1,3-thiazol-4-yl]-2-fluorophenyl}-3-furansulfonamide;    and    pharmaceutically acceptable salts thereof (particularly the free    base forms) for use in the treatment of a susceptible neoplasm    (e.g., Barret's adenocarcinoma; billiary tract carcinomas; breast    cancer; cervical cancer; cholangiocarcinoma; central nervous system    tumors including primary CNS tumors such as glioblastomas,    astrocytomas (e.g., glioblastoma multiforme) and ependymomas, and    secondary CNS tumors (i.e., metastases to the central nervous system    of tumors originating outside of the central nervous system);    colorectal cancer including large intestinal colon carcinoma;    gastric cancer; carcinoma of the head and neck including squamous    cell carcinoma of the head and neck; hematologic cancers including    leukemias and lymphomas such as acute lymphoblastic leukemia, acute    myelogenous leukemia (AML), myelodysplastic syndromes, chronic    myelogenous leukemia, Hodgkin's lymphoma, non-Hodgkin's lymphoma,    megakaryoblastic leukemia, multiple myeloma and erythroleukemia;    hepatocellular carcinoma; lung cancer including small cell lung    cancer and non-small cell lung cancer; ovarian cancer; endometrial    cancer; pancreatic cancer; pituitary adenoma; prostate cancer; renal    cancer; sarcoma; skin cancers including melanomas; and thyroid    cancers) in a mammal (e.g., human) in need thereof.

In another aspect of the present invention, there is provided apharmaceutical composition comprising a compound selected from

-   N-{3-[5-(2-amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide;-   N-{3-[2-(1,1-dimethylethyl)-5-(2-methyl-4-pyrimidinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide;-   N-{3-[5-(2-amino-4-pyrimidinyl)-2-(tetrahydro-2H-pyran-4-yl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide;-   N-{3-[5-(2-amino-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide;-   N-{3-[5-(2-amino-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]-2-chlorophenyl}-2-furansulfonamide;-   N-{3-[5-(2-amino-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]-2-chlorophenyl}-2,5-difluorobenzenesulfonamide;-   N-{3-[2-(1,1-dimethylethyl)-5-(4-pyrimidinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide;-   N-{3-[5-(2-amino-4-pyrimidinyl)-2-(tetrahydro-2H-pyran-4-yl)-1,3-thiazol-4-yl]-2-chlorophenyl}-3-furansulfonamide;-   N-{3-[5-(2-amino-4-pyrimidinyl)-2-(tetrahydro-2H-pyran-4-yl)-1,3-thiazol-4-yl]-2-fluorophenyl}-3-furansulfonamide;    and    pharmaceutically acceptable salts thereof (particularly the free    base forms) for use in the treatment of breast cancer,    cholangiocarcinoma, colorectal cancer, melanoma, non-small cell lung    cancer, ovarian cancer, or thyroid cancer in a mammal (e.g., human)    in need thereof.

These and other aspects of the invention are described further in theDetailed Description and Examples which follow.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is an X-Ray Powder Diffraction Pattern of a particular solidstate form ofN-{3-[5-(2-amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide.The XRD pattern is expressed in terms of 2 theta angles and obtainedwith a PANalytical diffractometer equipped with a diffracted beam nickelfilter using copper Kα X-radiation, according to the proceduresdescribed herein.

FIG. 2 is a differential scanning calorimetry (DSC) thermogram of aparticular solid state form ofN-{3-[5-(2-amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide.The DSC was carried out on a TA Instruments DSC Q100 system at a heatingrate of 10° C. per minute, using a sample size of 0.4-1.5 mg, accordingto the procedures described herein.

FIG. 3 is a is an X-Ray Powder Diffraction Pattern of a particular solidstate form ofN-{3-[5-(2-amino-4-pyrimidinyl)-2-(tetrahydro-2H-pyran-4-yl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide.The XRD pattern is expressed in terms of 2 theta angles and obtainedwith a PANalytical diffractometer equipped with a diffracted beam nickelfilter using copper Kα X-radiation, according to the proceduresdescribed herein.

FIG. 4 is a differential scanning calorimetry (DSC) thermogram of aparticular solid state form ofN-{3-[5-(2-amino-4-pyrimidinyl)-2-(tetrahydro-2H-pyran-4-yl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide.The DSC was carried out on a TA Instruments DSC Q100 system at a heatingrate of 10° C. per minute, using a sample size of 0.4-1.5 mg, accordingto the procedures described herein.

FIG. 5 is a is an X-Ray Powder Diffraction Pattern of a particular solidstate form ofN-{3-[2-(1,1-dimethylethyl)-5-(2-methyl-4-pyrimidinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide.The XRD pattern is expressed in terms of 2 theta angles and obtainedwith a PANalytical diffractometer equipped with a diffracted beam nickelfilter using copper Kα X-radiation, according to the proceduresdescribed herein.

FIG. 6 is a differential scanning calorimetry (DSC) thermogram of aparticular solid state form ofN-{3-[2-(1,1-dimethylethyl)-5-(2-methyl-4-pyrimidinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide.The DSC was carried out on a TA Instruments DSC Q100 system at a heatingrate of 10° C. per minute, using a sample size of 0.4-1.5 mg, accordingto the procedures described herein.

DETAILED DESCRIPTION OF THE INVENTION

As used herein, the term “Raf family kinase” refers to Raf kinasesincluding A-Raf, B-Raf and c-Raf (also known as Raf-1). Unlessdistinguished herein, the term refers to both wildtype and mutantvariations thereof.

As used herein, “compound(s) of formula (I)” means any compound havingthe structural formula (I) as defined by the variable definitionsprovided, possible solvates, including hydrates thereof, and amorphousand crystal forms, including one or more polymorphic forms and mixturesthereof. In the case of compounds of formula (I) which possess one ormore chiral centers, the compounds may be in the form of a racemicmixture, or one or more isomerically enriched or pure stereoisomers,including enantiomers and diastereomers thereof. In such embodiments,“compound(s) of formula (I)” includes the racemic form as well as theenriched or pure enantiomers and diastereomers. Enantiomericallyenriched or pure compounds will be designated using conventionalnomenclature, including the designations +, −, R, S, d, I, D and L,according to the predominant isomer present. Where a compound of theinvention contains an alkenyl or alkenylene group, cis (E) and trans (Z)isomerism may also occur. In such embodiments, “compound(s) of formula(I)” includes the individual stereoisomers of the compound of theinvention, which will be indicated using conventional, cis/transnomenclature. It should also be understood that compounds of formula (I)may exist in tautomeric forms other than that shown in the formula andalternative tautomeric forms are also included within “compound(s) offormula (I).”

As used herein, “compound(s) of the invention” means a compound offormula (I) (as defined above) in any version, i.e., as the free base oras a pharmaceutically acceptable salt thereof. The compound as anyversion may be in any form, including amorphous or crystalline forms,specific polymorphic forms, solvates, including hydrates (e.g., mono-,di- and hemi-hydrates), and mixtures of various forms.

Intermediates may also be present as salts. Thus, in reference tointermediates, the phrase “compound(s) of formula (number)” means acompound having that structural formula or a pharmaceutically acceptablesalt thereof.

The term “alkyl” as used herein refers to linear or branched hydrocarbonchains having from 1 to 8 carbon atoms, unless a different number ofatoms is specified. Examples of “alkyl” as used herein include, but arenot limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, n-pentyl,sec-butyl, isobutyl, and tert-butyl. The term “alkyl” and variationsthereof (i.e., “C₁₋₄alkyl”) is intended to independently describe eachmember of the genus. Similarly, the term “alkylene” refers to linear orbranched divalent hydrocarbon chains containing from 1 to 8 carbonatoms, unless a different number of atoms is specified. Examples of“alkylene” as used herein include, but are not limited to, methylene,ethylene, propylene, butylene, and isobutylene. The term “alkylene” andvariations thereof (i.e., “C₁₋₃alkylene”) is intended to independentlydescribe each member of the genus.

As used herein, the term “alkenyl” refers to linear or branchedhydrocarbon chains having from 2 to 8 carbon atoms, unless a differentnumber of atoms is specified, and at least one and up to threecarbon-carbon double bonds. Examples of “alkenyl” as used hereininclude, but are not limited to ethenyl and propenyl. The term “alkenyl”and variations thereof (i.e., “C₂₋₄alkenyl”) is intended toindependently describe each member of the genus.

As used herein, the term “cycloalkyl” refers to a saturated monocycliccarbocyclic ring having from 3 to 8 carbon atoms, unless a differentnumber of atoms is specified. “Cycloalkyl” includes by way of examplecyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl andcyclooctyl. Preferred cycloalkyl groups include substituted andunsubstituted C₃₋₆cycloalkyl. The term “cycloalkyl” and variationsthereof (i.e., “C₃₋₆cycloalkyl”) is intended to independently describeeach member of the genus.

The terms “halo” and “halogen” are synonymous and refer to fluoro,chloro, bromo and iodo. In particular embodiments, “halo” refers tofluoro and chloro.

As used herein, “haloalkyl” refers to an alkyl, as defined above,substituted by one or more halogen atoms, fluoro, chloro, bromo or iodo.Where the haloalkyl group has less than 8 carbon atoms, the number ofcarbon atoms in the group is indicated as, for example, “haloC₁₋₃alkyl”,which indicates that the haloalkyl group has 1, 2 or 3 carbon atoms.Examples of haloalkyl as used herein include, but are not limited tofluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl,trifluoroethyl, and the like. The term “haloalkyl” and variationsthereof (i.e., “haloC₁₋₃alkyl”) is intended to independently describeeach member of the genus.

The term “oxo” as used herein refers to the group ═O attached directlyto a carbon atom of a hydrocarbon ring (e.g., cycloalkyl orcycloalkenyl) or a C, N or S of a heterocyclic or heteroaryl ring toresult in oxides, N-oxides, sulfones and sulfoxides.

As used herein, the terms “heterocycle” and “heterocyclic” aresynonymous and refer to monocyclic saturated or unsaturated non-aromaticgroups, having from 4 to 6 members (unless a different number of membersis specified) and including 1, 2, or 3 heteroatoms selected from N, Oand S, unless a different number of heteroatoms is specified. In allembodiments wherein the heterocycle includes 2 or more heteroatoms, theheteroatoms may be the same or different and are independently selectedfrom N, O and S. In all embodiments wherein the compound of formula (I)includes two or more heterocyclic groups, the heterocyclic groups may bethe same or different and are independently selected. Examples ofparticular heterocyclic groups include but are not limited totetrahydrofuran, dihydropyran, tetrahydropyran, pyran, thietane,1,4-dioxane, 1,3-dioxane, 1,3-dioxalane, piperidine, piperazine,pyrrolidine, morpholine, thiomorpholine, thiazolidine, oxazolidine,tetrahydrothiopyran, tetrahydrothiophene and the like. The term“heterocycle” and variations thereof (i.e., “N-heterocycle”) is intendedto independently describe each member of the genus.

As used herein, the term “N-heterocycle” refers to monocyclic saturatedor unsaturated non-aromatic groups having from 4 to 6 members, includingat least one N and optionally 1 or 2 additional heteroatoms selectedfrom N, O and S, unless a different number of additional heteroatoms isspecified. By “additional heteroatoms” is meant 1 or 2 heteroatoms inaddition to the N already specified in the N-heterocycle ring. In allembodiments wherein the heterocycle includes 1 or more additionalheteroatoms, the heteroatoms may be the same or different and areindependently selected from N, O and S. N-heterocycles include bothgroups bound through the N of the N-heterocycle and groups bound througha C or S of the N-heterocycle. In all embodiments wherein the compoundof formula (I) includes two or more N-heterocyclic groups, theN-heterocyclic groups may be the same or different and are independentlyselected. Examples of N-heterocycles include piperidine, piperazine,pyrrolidine, morpholine, thiomorpholine and the like.

As used herein, the term “heteroaryl” refers to aromatic, monocyclicgroups having 5 or 6 members (unless a different number of members isspecified) including 1, 2 or 3 heteroatoms selected from N, O and S,unless a different number of heteroatoms is specified. In allembodiments wherein the heteroaryl includes 2 or more heteroatoms, theheteroatoms may be the same or different and are independently selectedfrom N, O and S. In all embodiments wherein the compound of formula (I)includes two or more heteroaryl groups, the heteroaryl groups may be thesame or different and are independently selected. Examples of particularheteroaryl groups include but are not limited to furan, thiophene,pyrrole, imidazole, pyrazole, triazole, tetrazole, thiazole, oxazole,isoxazole, oxadiazole, thiadiazole, isothiazole, pyridine, pyridazine,pyrazine, pyrimidine, and triazine. The term “heteroaryl” and variationsthereof (i.e., “N-heteroaryl”) is intended to independently describeeach member of the genus.

As used herein, the term “N-heteroaryl” refers to aromatic, monocyclicgroups having 5 or 6 members (unless a different number of members isspecified) including at least one N and optionally 1 or 2 additionalheteroatoms selected from N, O and S, unless a different number ofheteroatoms is specified. By “additional heteroatoms” is meant 1 or 2heteroatoms in addition to the N already specified in the N-heteroarylring. In all embodiments wherein the heteroaryl includes 1 or moreadditional heteroatoms, the heteroatoms may be the same or different andare independently selected from N, O and S. N-heteroaryls include bothgroups bound through the N of the N-heteroaryl and groups bound througha C or S of the N-heteroaryl. In all embodiments wherein the compound offormula (I) includes two or more N-heteroaryl groups, the N-heteroarylgroups may be the same or different and are independently selected.Examples of N-heteroaryls include pyrrole, imidazole, pyrazole,thiazole, isoxazole, pyridine, pyridazine, pyrazine, pyrimidine andtriazine.

As used herein, the term “members” (and variants thereof e.g.,“membered”) in the context of heterocyclic and heteroaryl groups refersto the total number of ring atoms, including carbon and heteroatoms N, Oand/or S. Thus, an example of a 6-membered heterocyclic ring ispiperidine and an example of a 6-membered heteroaryl ring is pyridine.

As used herein, the term “optionally substituted” means unsubstitutedgroups or rings (e.g., cycloalkyl, heterocycle, and heteroaryl rings)and rings substituted with one or more specified substituents.

Throughout this disclosure, a list of alternatives, such as thoseprovided above and below, is intended to particularly describe eachspecies individually as well as sub-groups of one or more species withinthe list of alternatives (e.g., “or subset thereof”).

The present invention provides compounds of formula (I):

wherein:

-   a is 0, 1, 2 or 3;-   each R¹ is the same or different and is independently selected from    halo, alkyl, haloalkyl, —OR⁶, —CO₂R⁶, —NR⁶R⁷, and —CN;-   Ring A is selected from C₃₋₆cycloalkyl, phenyl, 5-6 membered    heterocycle and 5-6 membered heteroaryl, said heterocycle and said    heteroaryl each having 1 or 2 heteroatoms selected from N, O and S;-   each of Q¹, Q², Q³ and Q⁴ is CH, C—R² or N, wherein not more than    one of Q¹, Q², Q³, and Q⁴ is N;-   each R² is the same or different and is independently selected from    halo, alkyl, haloalkyl, and —OR⁶;-   W is selected from —O— and —S—;-   R³ is selected from H, alkyl, haloalkyl-, -alkylene-OH, —NR⁶R⁷,    —C₃₋₆cycloalkyl, -alkylene-C(O)—OH, -alkylene-NH₂, and Het;    -   wherein said R³ C₃₋₆cycloalkyl is optionally substituted with 1        or 2 substituents which are the same or different and are        independently selected from halo, C₁₋₃alkyl, haloC₁₋₃alkyl, OH,        O—C₁₋₃alkyl, oxo, S(C₁₋₃alkyl), SO₂, NH₂, N(H)C₁₋₃alkyl and        N(C₁₋₃alkyl)₂;    -   Het is a 5-6 membered heterocycle having 1 or 2 heteroatoms        selected from N, O and S and optionally substituted with 1 or 2        substituents which are the same or different and are each        independently selected from halo, C₁₋₃alkyl, haloC₁₋₃alkyl,        O—C₁₋₃alkyl, C₁₋₃alkylene-O—C₁₋₃alkyl, OH, C₁₋₃alkylene-OH, oxo,        SO₂(C₁₋₃alkyl), C₁₋₃alkylene-SO₂(C₁₋₃alkyl), NH₂, N(H)C₁₋₃alkyl,        N(C₁₋₃alkyl)₂, CN, and —CH₂CN;        R⁴ is selected from H, alkyl, haloalkyl, alkenyl, —OR⁶, —R⁵—OR⁶,        —R⁵—CO₂R⁶, —R⁵—SO₂R⁶, —R⁵-Het, —R⁵—C(O)-Het, —N(H)R⁸, —N(CH₃)R⁸,        and —R⁵—NR⁶R⁷; each R⁵ is the same or different and is        independently C₁₋₄alkylene;        each R⁶ and each R⁷ is the same or different and is        independently selected from H, alkyl, haloalkyl, —C(O)-alkyl,        and —C(O)-cycloalkyl;-   R⁸ is selected from H, alkyl (optionally substituted by —OH),    haloalkyl, C₃₋₆cycloalkyl, —R⁵—C₃₋₆cycloalkyl, Het², —R⁵-Het²,    —R⁵—OR⁶, —R⁵—O—R⁵—OR⁶, —R⁵—C(O)₂R⁶, —R⁵—C(O)NR⁶R⁷, —R⁵—N(H)C(O)—R⁶,    —R⁵—N(H)C(O)—R⁵—OR⁶, —R⁵—N(H)C(O)₂—R⁶, —R⁵—NR⁶R⁷, —R⁵—S(O)₂R⁶,    —R⁵—CN, and —R⁵—N(H)S(O)₂R⁶;    -   wherein said R⁸ C₃₋₆cycloalkyl is optionally substituted with 1        or 2 substituents which are the same or different and are        independently selected from halo, C₁₋₃alkyl, haloC₁₋₃alkyl, OH,        O—C₁₋₃alkyl, oxo, S(C₁₋₃alkyl), SO₂(C₁₋₃alkyl), NH₂,        N(H)C₁₋₃alkyl and N(C₁₋₃alkyl)₂, and N(H)SO₂C₁₋₃alkyl; and    -   Het² is a 4-6 membered heterocycle having 1 or 2 heteroatoms        selected from N, O and S and optionally substituted with 1, 2,        3, 4 or 5 C₁₋₃alkyl or 1 or 2 substituents which are the same or        different and are each independently selected from halo,        C₁₋₃alkyl, haloC₁₋₃alkyl, O—C₁₋₃alkyl, C₁₋₃alkylene-O—C₁₋₃alkyl,        OH, C₁₋₃alkylene-OH, oxo, SO₂(C₁₋₃alkyl),        C₁₋₃alkylene-SO₂(C₁₋₃alkyl), NH₂, N(H)C₁₋₃alkyl, N(C₁₋₃alkyl)₂,        N(H)SO₂C₁₋₃alkyl, C(O)(C₁₋₃alkyl), CO₂(C₁₋₄alkyl), CN, and        —CH₂CN;        and R⁹ and R¹⁹ are independently selected from H and alkyl,        and pharmaceutically acceptable salts thereof.

For purposes of optimal clarity in distinguishing the cycloalkyl groupsdefining the variables R³ and R⁸ above, the language “R³ C₃₋₆cycloalkyl”is used to refer to the cycloalkyl group defining the variable R³ and“R⁸ C₃₋₆cycloalkyl” refers to the cycloalkyl group defining the variableR⁸.

The compounds of the invention are described in the conventional manneremploying variables to represent a number of possible substituents orgroups. The original, particular and preferred definitions of variablesdescribed herein apply equally to compounds of formula (I) and compoundsof the invention. For brevity, the following description will generallyrefer to “compounds of the invention” rather than to both, as compoundsof the invention encompasses all compounds of formula (I). For example,the organic chemist of ordinary skill in the art would appreciate thatmoieties such as —N(H)CH₂F, —N(H)CH₂NH₂, —OCH₂NH₂, and the like, resultin potentially unstable acetals, aminals or iminium ions. As such, thepresent invention should be understood such that the variables aredefined in a manner which avoids such embodiments.

In a particular embodiment, the compounds of the invention are definedwherein a is 0, 1 or 2. In another particular embodiment, a is 1 or 2.In one particular embodiment, a is 1. In another particular embodiment,a is 2. In those embodiments wherein Ring A is phenyl, particularembodiments are defined wherein a is 1 or 2, more particularly 2. Inembodiments wherein Ring A is 5-6 membered heterocycle or heteroaryl,particular embodiments are defined wherein a is 0 or 1, moreparticularly 0. In those embodiments wherein Ring A is cycloalkyl,particular embodiments are defined wherein a is 0.

In those embodiments of the compounds of the invention wherein a is 1, 2or 3, each R¹ may be bound to Ring A through any suitable carbon orheteroatom of Ring A (to provide, for example, N-methyl, N-oxides orsulfones). In certain embodiments, wherein a is any of 1, 2 or 3, eachR¹ is the same or different and is independently selected from halo(particularly F or Cl), alkyl, haloalkyl, and —OR⁶, or any subsetthereof. In those embodiments wherein R¹ is —OR⁶, where R⁶ is H, it willbe understood that when Ring A is a heterocycle or heteroaryl, thecompounds of the invention include the tautomeric form wherein theheterocycle or heteroaryl Ring A is substituted by oxo. Specificexamples of groups defining R¹ include but are not limited to F, Cl, Br,CH₃, CF₃, CH₂CH₃, CH(CH₃)₂, CH₂CH₂CH₃, OCH₃, OCF₃, OCH₂CH₃, andOCH₂CH₂CH₃. In one particular embodiment, each R¹ is the same ordifferent and is independently selected from F, Cl, C₁₋₃alkyl, CF₃, andOC₁₋₃alkyl, or any subset thereof. In one particular embodiment, each R¹is the same or different and is independently F, Cl, CH₃, CF₃, or OCH₃,or any subset thereof. In one preferred embodiment, each R¹ is the sameor different and is independently F, Cl, or CH₃, or any subset thereof.In one particular preferred embodiment, each R¹ is the same or differentand is independently F or Cl. In one particular preferred embodiment,each R¹ is F. In one preferred embodiment, a is 1 and R¹ is F. Inanother preferred embodiment, a is 2 and both R¹ are F.

in formula (I) is referred to herein as “Ring A.” Ring A is selectedfrom C₃₋₆cycloalkyl, phenyl, 5-6 membered heterocycle having 1 or 2heteroatoms selected from N, O and S and 5-6 membered heteroaryl having1 or 2 heteroatoms selected from N, O and S, or any subset thereof. RingA may be bonded to the sulfonyl through any suitable carbon orheteroatom of Ring A. In one embodiment, Ring A is selected from phenyl,5-6 membered heterocycle and 5-6 membered heteroaryl, or any subsetthereof. In one particular embodiment, Ring A is phenyl or 5-6 memberedheteroaryl having 1 or 2 heteroatoms selected from N, O and S. In oneembodiment, Ring A is phenyl or 5-6 membered N-heteroaryl. The 5-6membered N-heteroaryl may have no or 1 additional heteroatom selectedfrom N, O and S. In one preferred embodiment, Ring A is phenyl. Inanother particular embodiment, Ring A is a 5-6 membered heteroaryl,particularly N-heteroaryl optionally having 1 additional heteroatomselected from N, O and S. In another preferred embodiment, Ring A is5-membered heteroaryl, particularly a 5-membered heteroaryl having onlyone heteroatom which is selected from N, O and S.

Specific examples of groups defining Ring A include cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, phenyl, tetrahydrofuranyl,tetrahydropyranyl, pyrrolidinyl, pyrrolinyl, pyrazolidinyl, pyrazolinyl,imidazolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl,furanyl, pyranyl, thiophenyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl,isoxazolyl, thiazolyl, isothiazolyl, pyridinyl, pyrimidinyl, andpyridizinyl. In one embodiment, Ring A is selected from these specificgroups or any subset thereof. In another particular embodiment, Ring Ais selected from cyclopropyl, cyclohexyl, phenyl, morpholinyl, furanyl,thiophenyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl,thiazolyl, isothiazolyl, pyridinyl, pyrmidinyl and pyridizinyl, or anysubset thereof. In one preferred embodiment, Ring A is selected fromphenyl, morpholinyl, furanyl, thiophenyl, imidazolyl, thiazolyl,isothiazolyl, and pyridinyl, or any subset thereof. In one preferredembodiment, Ring A is phenyl, furanyl, thiophenyl, thiazolyl, orpyridinyl or any subset thereof. In one preferred embodiment, Ring A isphenyl, furanyl, thiazolyl or pyridinyl, or any subset thereof. In oneparticular preferred embodiment, Ring A is phenyl, furanyl or pyridinyl.In one preferred embodiment, Ring A is phenyl. In another preferredembodiment, Ring A is furanyl. In another preferred embodiment, Ring Ais pyridinyl.

The ring defined as

is a phenyl or pyridinyl ring wherein when the ring is a pyridinyl, theN of the pyridinyl ring may be at any of positions indicated by Q₁, Q₂,Q₃ and Q⁴. In one embodiment, each of Q¹, Q², Q³ and Q⁴ is CH, C—R² orN, wherein not more than one of Q¹, Q², Q³, and Q⁴ is N and at least twoof Q¹, Q², Q³ and Q⁴ are CH. In one embodiment, each of Q¹, Q², Q³ andQ⁴ is CH, C—R² or N, wherein not more than one of Q¹, Q², U Q³, and Q⁴is N and not more than one of Q¹, Q², Q³ and Q⁴ is C—R². In onepreferred embodiment, each of Q¹, Q², Q³, and Q⁴ is CH or C—R², and thusthe ring is a phenyl ring or substituted phenyl ring. In a particularversion of this embodiment, at least two of Q¹, Q², Q³ and Q⁴ is CH, andthus the ring is unsubstituted phenyl or phenyl substituted by 1 or twosubstituents R². In one embodiment, one of Q¹, Q², Q³ and Q⁴ is C—R² andthe other three are CH. In one preferred embodiment, each of Q¹, Q², andQ³ is CH and Q⁴ is C—R². In another preferred embodiment, each of Q¹,Q², and Q⁴ is CH and Q³ is C—R².

In another embodiment, one of Q¹, Q², Q³, and Q⁴ is N, and thus the ringis a pyridinyl or substituted pyridinyl ring. In one version of thisembodiment, at least two of Q¹, Q², Q³ and Q⁴ is CH. In a particularembodiment, one of Q¹, Q², Q³, and Q⁴ is N, and the remaining of Q¹, Q²,Q³, and Q⁴ is CH. In one particular embodiment, Q³ is N, and Q¹, Q², andQ⁴ are CH. In another particular embodiment, Q⁴ is N, and Q¹, Q², and Q³are CH.

Particular specific embodiments of the compounds of the invention areillustrated by formulas (I-i) and (I-ii):

wherein Q⁴ is CH or C—R² and all other variables are as defined herein.Thus, compounds of the invention include compounds of formula (I-i) and(I-ii) and pharmaceutically acceptable salts thereof. Other specificembodiments of the compounds of formula (I) wherein Q¹, Q², Q³, and Q⁴are as described above will be readily apparent to those skilled in theart.

In one preferred embodiment, the compounds of the invention are selectedfrom compounds of formula (I-i-a) and pharmaceutically acceptable saltsthereof:

wherein all variables are as defined herein.

In those embodiments where one or more of Q¹, Q², Q³ and Q⁴ is C—R²,each R² is the same or different and is independently halo, alkyl,haloalkyl, or —OR⁶, or any subset thereof. In one embodiment, each R² isthe same or different and is independently halo or C₁₋₃alkyl (i.e., anyof methyl, ethyl, propyl, or isopropyl), or any subset thereof. In oneembodiment, “halo” defining R² is F or Cl. In one embodiment, each R² isthe same or different and is independently halo. In one particularembodiment, each R² is the same or different and is independently F orCl. In one preferred embodiment, each R² is F.

Particular compounds of the invention are defined wherein each of Q¹,Q², and Q³ is CH and Q⁴ is C—F or C—Cl (illustrated generically asformula (I-i-a) above wherein R² is F or Cl). In one version of thisembodiment, Q⁴ is C—F. In another embodiment, the compounds of theinvention are defined wherein each of Q¹, Q², and Q⁴ is CH and Q³ is C—For C—Cl. In one version of this embodiment, Q³ is C—F.

In a particular embodiment, the compounds of formula (I) are definedwherein Ring A is phenyl, Q¹, Q², and Q³ are all CH and Q⁴ is C—R². Thisembodiment is illustrated as formula (I-i-b):

wherein all variables are as defined herein.

In one embodiment, compounds of the invention are defined wherein W isO. In one preferred embodiment the compounds of the invention aredefined wherein W is S. This embodiment is illustrated by formula(I-iii):

wherein all variables are as defined herein.

In one particular embodiment, W is S, each of Q¹, Q², and Q³ is CH andQ⁴ is CH or C—R². This embodiment is illustrated by formula (I-iii-a):

wherein Q⁴ is CH or C—R² and all other variables are as defined herein.

In one particular preferred version of this embodiment, Ring A isphenyl. This embodiment is illustrated by formula (I-iii-b):

wherein Q⁴ is CH or C—R² and all variables are as defined herein.

Other examples of embodiments of the compounds of the invention areillustrated by formulas (I-iii-c), (I-iii-d) and (I-iii-e):

wherein Q⁴ is CH or C—R² and all other variables are as defined herein.

In one embodiment the compounds of the invention are defined wherein, R³is alkyl, haloalkyl, unsubstituted C₃₋₆cycloalkyl, or Het, or any subsetthereof. In one particular embodiment, R³ is selected from alkyl or Het,or any subset thereof. In one particular embodiment, R³ is Het,particularly Het bound through N. In one preferred embodiment, R³ isalkyl. One particular embodiment of the compounds of the invention aredefined wherein R³ is selected from alkyl (particularly C₁₋₆alkyl),tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, pyrrolinyl,pyrazolidinyl, pyrazolinyl, imidazolinyl, imidazolidinyl, piperidinyl,piperazinyl, morpholinyl, or thiomorpholinyl, or any subset thereof. Inthis embodiment, the heterocyclic groups may be unsubstituted orsubstituted as described in the definition of “Het”. In one particularembodiment, R³ is selected from C₃₋₆alkyl (e.g., propyl, isopropyl,n-butyl, isobutyl, sec-butyl, tert-butyl (dimethylethyl), pentyl andhexyl), piperidinyl, piperazinyl, morpholinyl, and thiomorpholinyl, orany subset thereof. The piperidinyl, piperazinyl, morpholinyl, andthiomorpholinyl may be unsubstituted or substituted as described in thedefinition of “Het”.

In one preferred embodiment, R³ is alkyl, and particularly branchedC₃₋₆alkyl (particularly isopropyl, sec-butyl, isobutyl or tert-butyl, orany subset thereof). In one specific preferred embodiment, R³ isisopropyl or tert-butyl. In one specific embodiment, R³ is isopropyl. Inone specific embodiment, R³ is tert-butyl. In one specific embodiment,R³ is tetrahydropyranyl. In one specific embodiment, R³ is substitutedor unsubstituted morpholinyl, particularly unsubstituted morpholinyl.

Het (as employed in the definition of R³) is a 5-6 membered heterocyclehaving 1 or 2 heteroatoms selected from N, O and S and optionallysubstituted with 1 or 2 substituents which are the same or different andare each independently selected from halo, C₁₋₃alkyl, haloC₁₋₃alkyl,O—C₁₋₃alkyl, C₁₋₃alkylene-O—C₁₋₃alkyl, OH, C₁₋₃alkylene-OH, oxo,SO₂(C₁₋₃alkyl), C₁₋₃alkylene-SO₂(C₁₋₃alkyl), NH₂, N(H)C₁₋₃alkyl,N(C₁₋₃alkyl)₂, CN, and —CH₂CN, or any subset thereof. In one embodiment,Het in the definition of R³ is a 5-6 membered N-heterocycle optionallyhaving 1 additional heteroatom selected from N, O and S and optionallysubstituted as described above. In one particular embodiment, Het is a5-6 membered N-heterocycle having no additional heteroatoms andoptionally 1 substituent as described above. In one particularembodiment, Het is a 5-6 membered N-heterocycle bound through the N,optionally having 1 additional heteroatom selected from N, O and S, andoptionally substituted with 1 substituent as described above. In oneembodiment, Het is selected from optionally substitutedtetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, pyrrolinyl,pyrazolidinyl, pyrazolinyl, imidazolinyl, imidazolidinyl, piperidinyl,piperazinyl, morpholinyl, thiomorpholinyl, or any subset thereof,wherein the optional substituents are as recited above. In oneparticular embodiment, Het in the definition of R³ is substituted orunsubstituted piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, orany subset thereof. In one specific embodiment, R³ is tetrahydropyranyl.In one particular embodiment, R³ is substituted or unsubstitutedmorpholinyl.

The compounds of the invention are defined wherein R⁴ is H, alkyl,haloalkyl, alkenyl, —OR⁶, —R⁵—OR⁶, —R⁵—CO₂R⁶, —R⁵—SO₂R⁶, —R⁵-Het,—N(H)R⁸, —N(CH₃)R⁸ or —R⁵—NR⁶R⁷, or any subset thereof. In oneembodiment, R⁴ is H, alkyl, alkenyl, —OR⁶, —R⁵—OR⁶, —R⁵—CO₂R⁶,—R⁵—SO₂R⁶, —N(H)R⁸, —N(CH₃)R⁸, or —R⁵—NR⁶R⁷, or any subset thereof. Inone embodiment, R⁴ is —R⁵-Het, wherein R⁵ is C₁₋₃alkylene and Het is a 6membered heterocycle having 1 or 2 heteroatoms selected from N, O and Sand optionally substituted with 1 or 2 substituents which are the sameor different and are each independently selected from halo, C₁₋₃alkyl,haloC₁₋₃alkyl, O—C₁₋₃alkyl, C₁₋₃alkylene-O—C₁₋₃alkyl, OH,C₁₋₃alkylene-OH, oxo, SO₂(C₁₋₃alkyl), C₁₋₃alkyleneSO₂(C₁₋₃alkyl), NH₂,N(H)C₁₋₃alkyl, N(C₁₋₃alkyl)₂, CN and —CH₂—CN, or any subset thereof. Inone particular embodiment, R⁴ is —R⁵-Het, wherein R⁵ is C₁₋₃alkylene andHet is a 6 membered N-heterocycle optionally having 1 additionalheteroatom selected from N, O and S and optionally substituted with 1 or2 substituents which are the same or different and are eachindependently selected from C₁₋₃alkyl, OH, and oxo, or any subsetthereof. In one embodiment, the N-heterocycle is bound through the N. Inone embodiment, R⁴ is —R⁵—NR⁶R⁷, wherein R⁵ is C₁₋₃alkylene and R⁶ andR⁷ are each independently H or alkyl, particularly H or C₁₋₃alkyl.

In one embodiment, R⁴ is H, alkyl, N(H)R⁸ or N(CH₃)R⁸, or any subsetthereof. In one particular embodiment, R⁴ is H, alkyl, or N(H)R⁸, or anysubset thereof.

The compounds of the invention, wherein R⁴ is H, are illustrated byformula (I-iv):

wherein all variables are as defined here.

Within this embodiment, particular embodiments of the compounds of theinvention wherein R⁴ is H, are illustrated by formulas (I-iv-a),(I-iv-b), (I-iv-c), (I-iv-d) and (I-iv-e):

wherein Q⁴ is CH or C—R² and all other variables are as defined herein.

Those skilled in the art will readily envision structural formulasillustrating compounds of the invention wherein R⁴ is H based upon theforegoing description and examples provided.

In another particular embodiment, the compounds of the invention aredefined wherein R⁴ is alkyl. This embodiment is illustrated by formula(I-v):

wherein all variables are as defined here.

Within this embodiment, particular embodiments of the compounds of theinvention wherein R⁴ is alkyl, are illustrated by formulas (I-v-a),(I-v-b), (I-v-c), (I-v-d) and (I-v-e):

wherein Q⁴ is CH or C—R² and all other variables are as defined herein.

Those skilled in the art will readily envision structural formulasillustrating compounds of the invention wherein R⁴ is alkyl based uponthe foregoing description and examples provided.

In one embodiment, R⁴ is C₁₋₄alkyl (i.e., methyl, ethyl, propyl,isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl). In one preferredembodiment, R⁴ is methyl.

In one particular embodiment R⁴ is N(H)R⁸ or N(CH₃)R⁸. In one preferredembodiment, R⁴ is N(H)R⁸, illustrated as formula (I-yl):

Within this embodiment, particular embodiments of the compounds of theinvention wherein R⁴ is N(H)R⁸, are illustrated by formulas (I-vi-a),(I-vi-b), (I-vi-c), (I-vi-d), (I-vi-e), (I-vi-f), (I-vi-g), (I-vi-h),(I-vi-j), and (I-vi-k):

wherein in formulas (I-vi-a), (I-vi-b), (I-vi-f), (I-vi-g), (I-vi-h),(I-vi-j), and (I-vi-k), Q⁴ is CH or C—R², and all other variables are asdefined herein.

The compounds of the invention are defined wherein R⁸ is selected fromH, alkyl, haloalkyl, C₃₋₆cycloalkyl, —R⁵—C₃₋₆cycloalkyl, Het², —R⁵-Het²,—R⁵—OR⁶, —R⁵—O—R⁵—OR⁶, —R⁵—C(O)₂R⁶, —R⁵—C(O)NR⁶R⁷, —R⁵—N(H)C(O)—R⁶,—R⁵—N(H)C(O)—R⁵—OR⁶, —R⁵—N(H)C(O)₂—R⁶, —R⁵—NR⁶R⁷, —R⁵—S(O)₂R⁶, and—R⁵—N(H)S(O)₂R⁶, or any subset thereof;

-   wherein the R⁸ C₃₋₆cycloalkyl is optionally substituted with 1 or 2    substituents which are the same or different and are independently    selected from halo, C₁₋₃alkyl, haloC₁₋₃alkyl, OH, O—C₁₋₃alkyl, oxo,    S(C₁₋₃alkyl), SO₂(C₁₋₃alkyl), NH₂, N(H)C₁₋₃alkyl and N(C₁₋₃alkyl)₂,    and N(H)SO₂C₁₋₃alkyl; and-   Het² is a 4-6 membered heterocycle having 1 or 2 heteroatoms    selected from N, O and S and optionally substituted with 1, 2, 3, 4    or 5 C₁₋₃alkyl or 1 or 2 substituents which are the same or    different and are each independently selected from halo, C₁₋₃alkyl,    haloC₁₋₃alkyl, O—C₁₋₃alkyl, C₁₋₃alkylene-O—C₁₋₃alkyl, OH,    C₁₋₃alkylene-OH, oxo, SO₂(C₁₋₃alkyl), C₁₋₃alkylene-SO₂(C₁₋₃alkyl),    NH₂, N(H)C₁₋₃alkyl, N(C₁₋₃alkyl)₂, N(H)SO₂C₁₋₃alkyl,    C(O)(C₁₋₃alkyl), CO₂(C₁₋₄alkyl), CN, and —CH₂CN;

In one embodiment, R⁸ is selected from H, alkyl, haloalkyl,C₃₋₆cycloalkyl, —R⁵—C₃₋₆cycloalkyl, Het², —R⁵-Het², —R⁵—OR⁶,—R⁵—O(CH₂)₂OR⁶, —R⁵—C(O)NR⁶R⁷, —R⁵—N(H)C(O)—R⁶, —R⁵—N(H)C(O)CH₂OH,—R⁵—C(O)₂R⁶, —R⁵—N(H)C(O)₂—R⁶, —R⁵—NR⁶R⁷, —R⁵—S(O)₂R⁶, and—R⁵—N(H)S(O)₂R⁶, or any subset thereof.

In another particular embodiment, R⁸ is selected from H, alkyl,haloalkyl, unsubstituted cyclopropyl, optionally substituted cyclohexyl,—R⁵—C₃₋₆cycloalkyl, —R⁵-Het², —R⁵—OR⁶, —R⁵—C(O)₂R⁶, —R⁵—C(O)NR⁶R⁷,—R⁵—N(H)C(O)—R⁶, —R⁵—NR⁶R⁷, and —R⁵—S(O)₂R⁶, or any subset thereof. Inone particular embodiment, R⁸ is selected from H, alkyl, haloalkyl,unsubstituted cyclopropyl, optionally substituted cyclohexyl, —R⁵-Het²,—R⁵—OR⁶, and —R⁵—S(O)₂R⁶, or any subset thereof.

In one particular embodiment, the compounds of the invention are definedwherein R⁸ is selected from H, alkyl, haloalkyl, C₃₋₆cycloalkyl,—R⁵—C₃₋₆cycloalkyl, —R⁵—OR⁶, —R⁵—O—R⁵—OR⁶, —R⁵—C(O)₂R⁶, —R⁵—C(O)NR⁶R⁷,—R⁵—N(H)C(O)—R⁶, —R⁵—N(H)C(O)—R⁵—OR⁶, —R⁵—N(H)C(O)₂—R⁶, —R⁵—NR⁶R⁷,—R⁵—S(O)₂R⁶, and —R⁵—N(H)S(O)₂R⁶, or any subset thereof.

In one particular embodiment, R⁸ is selected from H, alkyl, haloalkyl,C₃₋₆cycloalkyl, —R⁵—C₃₋₆cycloalkyl, —R⁵—OR⁶, —R⁵—O(CH₂)₂OR⁶,—R⁵—C(O)₂R⁶, —R⁵—C(O)NR⁶R⁷, —R⁵—N(H)C(O)—R⁶, —R⁵—N(H)C(O)CH₂OH,—R⁵—N(H)C(O)₂—R⁶, —R⁵—NR⁶R⁷, —R⁵—S(O)₂R⁶, —R⁵—N(H)S(O)₂R⁶, or any subsetthereof.

In another embodiment, R⁸ is selected from H, alkyl, haloalkyl,unsubstituted cyclopropyl, optionally substituted cyclohexyl,—R⁵—C₃₋₆cycloalkyl, —R⁵—OR⁶, —R⁵—C(O)₂R⁶, —R⁵—C(O)NR⁶R⁷,—R⁵—N(H)C(O)—R⁶, —R⁵—NR⁶R⁷, and —R⁵—S(O)₂R⁶, or any subset thereof.

In one particular embodiment, R⁸ is selected from H, alkyl, haloalkyl,unsubstituted cyclopropyl, optionally substituted cyclohexyl, —R⁵—OR⁶,and —R⁵—S(O)₂R⁶, or any subset thereof.

In one embodiment, R⁸ C₃₋₆cycloalkyl is optionally substitutedcyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl or any subsetthereof, wherein the optional substituents are as defined above. In oneparticular embodiment, R⁸ C₃₋₆cycloalkyl is unsubstituted cyclopropyl,unsubstituted cyclobutyl or optionally substituted cyclohexyl. In oneparticular embodiment, R⁸ C₃₋₆cycloalkyl is unsubstituted cyclopropyl,unsubstituted cyclobutyl, unsubstituted cyclohexyl or cyclohexylsubstituted once by N(H)S(O)₂CH₃.

In another embodiment, R⁸ is Het² or —R⁵-Het², or any subset thereof. Inone particular embodiment, R⁸ is —R⁵-Het², such as CH₂-Het², or(CH₂)₂-Het².

In one embodiment, R⁸ is defined wherein Het² (including as R⁵-Het²) isa 5-6 membered heterocycle having 1 or 2 heteroatoms selected from N, Oand S and optionally substituted with 1, 2, 3, 4 or 5 C₁₋₃alkyl (whichare the same or different), or 1 or 2 substituents which are the same ordifferent and are each independently selected from halo, C₁₋₃alkyl,haloC₁₋₃alkyl, O—C₁₋₃alkyl, C₁₋₃alkylene-O—C₁₋₃alkyl, OH,C₁₋₃alkylene-OH, oxo, SO₂(C₁₋₃alkyl), C₁₋₃alkylene-SO₂(C₁₋₃alkyl), NH₂,N(H)C₁₋₃alkyl, N(C₁₋₃alkyl)₂, N(H)SO₂C₁₋₃alkyl, C(O)(C₁₋₃alkyl),CO₂(C₁₋₄alkyl), CN, and —CH₂CN

More particularly Het² is a 5-6 membered heterocycle optionallysubstituted with 1, 2, 3, 4, or 5 methyl or ethyl, more particularlymethyl. In another embodiment, Het² is a 5-6 membered heterocycle having1 or 2 heteroatoms selected from N, O and S and optionally substitutedwith 1 or 2 substituents which are the same or different and areindependently selected from halo, C₁₋₃alkyl, haloC₁₋₃alkyl, O—C₁₋₃alkyl,C₁₋₃alkylene-O—C₁₋₃alkyl, OH, C₁₋₃alkylene-OH, oxo, SO₂(C₁₋₃alkyl),C₁₋₃alkylene-SO₂(C₁₋₃alkyl), NH₂, N(H)C₁₋₃alkyl, N(C₁₋₃alkyl)₂,N(H)SO₂C₁₋₃alkyl, C(O)(C₁₋₃alkyl), CO₂(C₁₋₄alkyl), CN, and —CH₂CN, orany subset thereof.

In certain embodiments of the invention, the group Het² isunsubstituted. In those embodiments wherein Het² is substituted by 1 or2 substituents as described above, a particular embodiment is definedwherein the substituent(s) is/are selected from C₁₋₃alkyl,haloC₁₋₃alkyl, O—C₁₋₃alkyl, C₁₋₃alkylene-OH, oxo, SO₂(C₁₋₃alkyl),C₁₋₃alkylene-SO₂(C₁₋₃alkyl), NH₂, N(H)C₁₋₃alkyl, N(C₁₋₃alkyl)₂,C(O)(C₁₋₃alkyl), and CH₂—CN, or any subset thereof. In a more particularembodiment, the optional substituent(s) on Het² is/are selected fromC₁₋₃alkyl, haloC₁₋₃alkyl, O—C₁₋₃alkyl, C₁₋₃alkylene-OH, oxo,SO₂(C₁₋₃alkyl), C₁₋₃alkylene-SO₂(C₁₋₃alkyl), C(O)(C₁₋₃alkyl), andC₁₋₃alkylene-CN, or any subset thereof. In one particular embodiment,the optional substituent(s) on Het² is/are selected from C₁₋₃alkyl, oxo,SO₂(C₁₋₃alkyl), C₁₋₃alkylene-SO₂(C₁₋₃alkyl), NH₂, N(H)C₁₋₃alkyl,N(C₁₋₃alkyl)₂, C(O)(C₁₋₃alkyl), and CO₂(C₁₋₄alkyl), or any subsetthereof. In one particular embodiment, Het² is a 5-6 memberedN-heterocycle optionally including 1 additional heteroatom selected fromN, O and S and optionally substituted with 1 or 2 substituents asdefined above.

Specific examples of groups defining Het² (including R⁵-Het²) within thedefinition of R⁸ include but are not limited to:

or any subset thereof. The point of attachment to the amine (NH) or theC₁₋₄alkylene (R⁵), in the case of R⁵-Het², is indicated by the unfilledbond.

In one preferred embodiment, the compounds of the invention are definedwherein R⁸ is H, C₁₋₄alkyl or haloC₁₋₄alkyl. In one preferredembodiment, R⁸ is H. In another preferred embodiment, R⁸ is C₁₋₄alkyl,including each of methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl,sec-butyl, and t-butyl. In one particular preferred embodiment, R⁸ isisopropyl or isobutyl. In another preferred embodiment, R⁸ ishaloC₁₋₄alkyl, particularly fluoroC₁₋₄alkyl or chloroC₁₋₄alkyl, moreparticularly fluoroC₁₋₄alkyl. Particular examples of fluoroC₁₋₄alkylgroups include fluoroethyl, difluoroethyl, trifluoroethyl, andethyltrifluoromethyl,

The alkylene group represented by R⁵, may be linear or branched. In oneembodiment, the compounds of the invention are defined wherein R⁵ ismethylene or ethylene, including —CH(CH₃)—.

In one embodiment, the compounds of the invention are defined wherein R⁶and R⁷ are the same or different and are each independently selectedfrom H, C₁₋₃alkyl and haloC₁₋₃alkyl, or any subset thereof. In oneembodiment, R⁶ and R⁷ are the same or different and are eachindependently selected from H, C₁₋₃alkyl.

In one preferred embodiment, the compounds of the invention arecompounds of formula (I-vii) or pharmaceutically acceptable saltsthereof:

wherein Q⁴ is CH or C—R² and all other variables are as defined herein.

In one preferred embodiment, the compounds of the invention arecompounds of formula (I-viii) or pharmaceutically acceptable saltsthereof:

wherein Q⁴ is CH or C—R² and all other variables are as defined herein.

In one preferred embodiment, the compounds of the invention arecompounds of formula (I-ix) or pharmaceutically acceptable saltsthereof:

wherein Q⁴ is CH or C—R² and all other variables are as defined herein.

In one preferred embodiment, the compounds of the invention arecompounds of formula (I-x) or pharmaceutically acceptable salts thereof:

wherein Q⁴ is CH or C—R² and all other variables are as defined herein.

It is to be understood that the present invention includes allcombinations and subsets of the particular and/or preferred groupsdefined hereinabove.

Specific examples of compounds of the present invention include thoserecited in the Examples which follow as well as pharmaceuticallyacceptable salts of compounds exemplified as the free base and otherpharmaceutically acceptable salts of those compounds exemplified assalts.

Preferred compounds of formula (I) are selected from:

and pharmaceutically acceptable salts thereof. In one embodiment, theforegoing compounds are in the form of the free base.

In particular, preferred compounds of formula (I) include but are notlimited to:

and pharmaceutically acceptable salts thereof. In one embodiment, theforegoing compounds are in the form of the free base.

One example of a more preferred compound of formula (I) isN-{3-[5-(2-amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide,

and pharmaceutically acceptable salts thereof. In one embodiment, thecompound is the free base. In another embodiment, the compound is apharmaceutically acceptable salt form thereof, selected from themesylate, sulfate, hydrochloride and sodium salt forms of the compound.

Another example of a more preferred compound of formula (I) isN-{3-[2-(1,1-dimethylethyl)-5-(2-methyl-4-pyrimidinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide,

and pharmaceutically acceptable salts thereof. In one embodiment, thecompound is the free base. In another embodiment, the compound is apharmaceutically acceptable salt form thereof, selected from themesylate, sulfate, hydrochloride and sodium salt forms of the compound.

Another example of a more preferred compound of formula (I) isN-{3-[5-(2-amino-4-pyrimidinyl)-2-(tetrahydro-2H-pyran-4-yl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide

and pharmaceutically acceptable salts thereof. In one embodiment, thecompound is the free base. In another embodiment, the compound is apharmaceutically acceptable salt form thereof, selected from themesylate, sulfate, hydrochloride and sodium salt forms of the compound.

With regard to compounds of formula (I-iv-k) discussed above

particularly preferred embodiments of the compounds are those of(I-iv-k1) and (I-iv-k2),

According to one embodiment of the invention, compounds of formula (I)are provided

wherein:

-   a is 0, 1, 2 or 3;-   each R¹ is the same or different and is independently selected from    halo, alkyl, haloalkyl, —OR⁶, —CO₂R⁶, —NR⁶R⁷, and —CN;-   Ring A is selected from C₃₋₆cycloalkyl, phenyl, 5-6 membered    heterocycle and 5-6 membered heteroaryl, said heterocycle and said    heteroaryl each having 1 or 2 heteroatoms selected from N, O and S;-   each of Q¹, Q², Q³ and Q⁴ is CH, C—R² or N, wherein not more than    one of Q¹, Q², Q³, and Q⁴ is N;-   each R² is the same or different and is independently halo, alkyl,    haloalkyl, or —OR⁶;-   W is —O— or —S—;-   R³ is H, alkyl, haloalkyl, alkylene-OH, NR⁶R⁷, C₃₋₆cycloalkyl, or    Het;    -   wherein said R³ C₃₋₆cycloalkyl is optionally substituted with 1        or 2 substituents which are the same or different and are        independently selected from halo, C₁₋₃alkyl, haloC₁₋₃alkyl, OH,        O—C₁₋₃alkyl, oxo, S(C₁₋₃alkyl), SO₂, NH₂, N(H)C₁₋₃alkyl and        N(C₁₋₃alkyl)₂;    -   Het is a 5-6 membered heterocycle having 1 or 2 heteroatoms        selected from N, O and S and optionally substituted with 1 or 2        substituents which are the same or different and are each        independently selected from halo, C₁₋₃alkyl, haloC₁₋₃alkyl,        O—C₁₋₃alkyl, C₁₋₃alkylene-O—C₁₋₃alkyl, OH, C₁₋₃alkylene-OH, oxo,        SO₂(C₁₋₃alkyl), C₁₋₃alkylene-SO₂(C₁₋₃alkyl), NH₂, N(H)C₁₋₃alkyl,        N(C₁₋₃alkyl)₂, CN, and —CH₂CN;-   R⁴ is H, alkyl, haloalkyl, alkenyl, —OR⁶, —R⁵—OR⁶, —R⁵—CO₂R⁶,    —R⁵—SO₂R⁶, —R⁵-Het, —N(H)R⁸, —N(CH₃)R⁸, or —R⁵—NR⁶R⁷;-   each R⁵ is the same or different and is independently C₁₋₄alkylene;-   each R⁶ and each R⁷ is the same or different and is independently H,    alkyl or haloalkyl;    and-   R⁸ is selected from H, alkyl, haloalkyl, C₃₋₆cycloalkyl,    —R⁵—C₃₋₆cycloalkyl, Het², —R⁵-Het², —R⁵—OR⁶, —R⁵—O—R⁵—OR⁶,    —R⁵—C(O)₂R⁶, —R⁵—C(O)NR⁶R⁷, —R⁵—N(H)C(O)—R⁶, —R⁵—N(H)C(O)—R⁵—OR⁶,    —R⁵—N(H)C(O)₂—R⁶, —R⁵—NR⁶R⁷, —R⁵—S(O)₂R⁶, and —R⁵—N(H)S(O)₂R⁶;    -   wherein said R⁸ C₃₋₆cycloalkyl is optionally substituted with 1        or 2 substituents which are the same or different and are        independently selected from halo, haloC₁₋₃alkyl, OH, oxo,        S(C₁₋₃alkyl), SO₂, NH₂, N(H)C₁₋₃alkyl and N(C₁₋₃alkyl)₂, and        N(H)SO₂C₁₋₃alkyl; and    -   Het² is a 4-6 membered heterocycle having 1 or 2 heteroatoms        selected from N, O and S and optionally substituted with 1, 2,        3, 4 or 5 C₁₋₃alkyl or 1 or 2 substituents which are the same or        different and are each independently selected from halo,        C₁₋₃alkyl, C₁₋₃alkylene-O—C₁₋₃alkyl, OH, C₁₋₃alkylene-OH, oxo,        SO₂(C₁₋₃alkyl), C₁₋₃alkylene-SO₂(C₁₋₃alkyl), NH₂, N(H)C₁₋₃alkyl,        N(C₁₋₃alkyl)₂, N(H)SO₂C₁₋₃alkyl, C(O)(C₁₋₃alkyl),        CO₂(C₁₋₄alkyl), CN, and —CH₂CN;        and a pharmaceutically acceptable salts thereof.

It will be appreciated by those skilled in the art that the compounds offormula (I) may be utilized as a pharmaceutically acceptable saltversion thereof. The pharmaceutically acceptable salts of the compoundsof formula (I) include conventional salts formed from pharmaceuticallyacceptable (i.e., non-toxic) inorganic or organic acids or bases as wellas quaternary ammonium salts. Representative salts include thefollowing: acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate,bitartrate, borate, bromide, calcium edetate, camsylate, carbonate,chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate,estolate, esylate, ethanol amine, fumarate, gluceptate, gluconate,glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine,hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate,lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate(methanesulfonate), methylbromide, methylnitrate, methylsulfate,monopotassium maleate, mucate, napsylate, nitrate, N-methylglucamine,oxalate, pamoate (embonate), palmitate, pantothenate,phosphate/diphosphate, polygalacturonate, potassium, salicylate, sodium,stearate, subacetate, succinate, tannate, tartrate, teoclate, tosylate(methylbenzenesulfonate), triethiodide, trimethylammonium and valerate.Other salts, such as oxalic and trifluoroacetic, which are notthemselves pharmaceutically acceptable, may be useful in the preparationof salts useful as intermediates in obtaining compounds of thisinvention and these form a further aspect of the invention. In oneembodiment, the compound of formula (I) is in the form of the free base.In one embodiment, the compound of formula (I) is in the form of themesylate salt. In one embodiment, the compound of formula (I) is in theform of the sulfate salt. In one embodiment, the compound of formula (I)is in the form of the hydrochloride salt. In one embodiment, thecompound of formula (I) is in the form of the sodium salt. Certain saltversions of the compounds may be solvates, particularly hydrates. In oneembodiment, the compound of formula (I) or a pharmaceutically acceptablesalt thereof is in the form of a mono-, di-, tri- or hemi-hydrate.

Processes for preparing pharmaceutically acceptable salts of compoundssuch as the compounds of formula (I) are conventional in the art. See,e.g., Burger's Medicinal Chemistry And Drug Discovery 5th Edition, Vol1: Principles And Practice. As will be apparent to those skilled in theart, in the processes described below for the preparation of compoundsof formula (I), certain intermediates, may be in the form ofpharmaceutically acceptable salts of the compound. Processes forpreparing pharmaceutically acceptable salts of intermediates are knownin the art and are analogous to the processes for preparingpharmaceutically acceptable salts of other compounds such as thecompounds of formula (I).

Compounds of the invention are believed to inhibit of one or morekinases and in particular one or more Raf family kinases (“Rafinhibitor”). Compounds of the invention may also inhibit one or moreother kinases, and particularly tyrosine kinases. Certain compounds ofthe invention may inhibit B-Raf (“B-Raf inhibitor”). It is welldocumented that Raf inhibitors, including B-Raf inhibitors, are believedto be useful as anticancer and antitumor agents. See, e.g., Davies(2002) supra, Garnett (2004) supra, and Zebisch (2006) supra. Theanticancer and antitumor effects of these kinase inhibitors is currentlybelieved to result from inhibition of one or more Raf family kinases,and the effect of such inhibition on cell lines whose growth and/orviability is dependent on the kinase activity of Raf family kinases.

Compounds of the invention may be Raf inhibitors and optionally alsoinhibit one or more ErbB family kinases (i.e., EGFR, ErbB2 and ErbB4).Certain compounds of the invention may inhibit B-Raf and also inhibitone or more ErbB family kinases (i.e., EGFR, ErbB2 and ErB4).

Some compounds of the invention may be selective inhibitors of Raffamily kinases (“selective Raf inhibitor”), meaning that preferentialinhibition of one or more Raf family kinases is significantly greaterthan that of any number of other kinases, for example by a factor of5-fold or more.

However, the present invention is not limited to compounds which areselective inhibitors of one or more Raf family kinases rather, thepresent invention expressly contemplates that certain compounds of theinvention may possess activity against multiple kinases, includingkinases other than Raf family kinases. For example, particular compoundsof the invention may possess activity against multiple other kinases,including but not limited to EGFR, ErbB2, ErbB4, IGF-1R, IR, IRR, Src,VEGFR, PDGFR, Met, Lyn, Lck, Alk5, Aurora A and B, JNK, Syk, p38, BTK,FAK, Abl, CK1. cKit, Epherin receptors (for example EphB4), FGFR, Flt,Fyn, Hck, JAK, MLK, PKCμ, Ret, Yes, and BRK, as well. Particularcompounds of the invention may be deemed to be unselective ornon-selective, meaning that they are not considered by one skilled inthe art to be selective for any particular kinase over others.

As used herein, a Raf inhibitor is a compound that exhibits a pIC₅₀ ofgreater than about 6 against at least one Raf family kinase in the Rafinhibition enzyme assay described below and/or an IC₅₀ of not greaterthan about 5 μM potency against at least one cell line that expressesmutated B-Raf kinase (e.g., A375P, Colo205, HT-29, SK-MEL-3, SK-MEL-28)in the methylene blue and/or the CellTiter-Glo cellular proliferationassays described below. In a particular embodiment, a Raf inhibitorrefers to a compound of the invention that exhibits a pIC₅₀ of greaterthan about 6.5 against at least one Raf family kinase in the Rafinhibition enzyme assay described below and an IC₅₀ of not greater thanabout 500 nM potency against at least one cell line that expressesmutated B-Raf kinase in the methylene blue and/or the CellTiter-Glocellular proliferation assays described below.

A “B-Raf inhibitor” refers to a compound of the invention that exhibitsa pIC₅₀ of greater than about 6.5 against B-Raf (including B-Rafmutants) in the Raf inhibition enzyme assay described below and an IC₅₀of not greater than about 500 nM potency against at least one cell linethat expresses mutated B-Raf kinase in the methylene blue and/or theCellTiter-Glo cellular proliferation assay described below.

The present invention provides compounds for use in medical therapy in amammal, e.g., a human, in need thereof. The present invention providesmethods for the treatment of several conditions in a mammal, in needthereof, all of which comprise the step of administering atherapeutically effective amount of a compound of the invention. Allmethods described herein are applicable to mammals, and particularly tohumans.

As used herein, the term “treatment” or “treating” in the context oftherapeutic methods, refers to alleviating the specified condition,eliminating or reducing the symptoms of the condition, slowing oreliminating the progression, invasion, or metastatic spread of thecondition and preventing or delaying the reoccurrence of the conditionin a previously afflicted subject. The present invention furtherprovides use of the compounds of the invention for the preparation of amedicament for the treatment of several conditions in a mammal (e.g.,human) in need thereof.

More particularly, the present invention provides compounds for use inthe treatment of a condition mediated by at least one Raf family kinases(e.g., B-Raf) in a mammal in need thereof. The present inventionprovides a method for treating a condition mediated by at least one Raffamily kinase (e.g., B-Raf) in a mammal (e.g., a human) in need thereof,which method comprises administering to the mammal a therapeuticallyeffective amount of the compound of the invention.

In another embodiment, the invention provides compounds for use inregulating, modulating, binding or inhibiting one or more Raf familykinases (e.g., B-Raf) in a mammal. The invention also provides methodsof regulating, modulating, binding, or inhibiting at least one Raffamily kinase (e.g., B-Raf) by administering a therapeutically effectiveamount of a compound of the invention. “Regulating, modulating, bindingor inhibiting at least one Raf family kinase” refers to regulating,modulating, binding or inhibiting the activity of at least one Raffamily kinase, as well as regulating, modulating, binding or inhibitingoverexpression of an upstream regulator of at least one Raf familykinase in order to inhibit the cellular potency of its signalingability.

In a particular embodiment, the invention provides compounds for use inthe treatment of a condition mediated by inappropriate activity of oneor more Raf family kinases (e.g., B-Raf), or an upstream activator ofone or more Raf family kinases in a mammal. The invention furtherprovides methods for the treatment of a condition mediated byinappropriate activity of one or more Raf family kinases (particularlyB-Raf), in a mammal in need thereof, comprising administering to themammal, a therapeutically effective amount of a compound of theinvention. In an additional aspect, the present invention provides theuse of a compound of the invention for the preparation of a medicamentfor the treatment of a condition mediated by inappropriate activity ofone or more Raf family kinases (particularly B-Raf), in a mammal. Oneexample of a condition mediated by inappropriate activity of one or moreRaf family kinases includes neoplasms.

By “inappropriate activity” is meant Raf family kinase activity thatdeviates from the expected activity for that kinase or for an upstreamactivator of that kinase in a particular mammal. The inappropriateactivity of a Raf family kinase may arise from one or more of A-Raf,B-Raf or c-Raf or an upstream activator of a Raf family kinase.Inappropriate Raf family kinase activity may take the form of, forinstance, an abnormal increase in activity, or an aberration in thetiming and/or control of Raf family kinase activity. Such inappropriateactivity may result, for example, from overexpression or mutation of thekinase, upstream activator, receptor or ligand leading to inappropriateor uncontrolled activation of the corresponding kinase or receptor.Furthermore, it is also contemplated that unwanted Raf family kinaseactivity may reside in an abnormal source, such as a neoplasm. Thus, thelevel of Raf family kinase activity does not need to be abnormal to beconsidered inappropriate in the case where the activity derives from anabnormal source including, but not limited to, upstream activators(e.g., activated mutant Ras GTPases) or neoplasm. In one example ofinappropriate Raf family kinase activity not resulting from mutation oroverexpression of a Raf family kinase, inappropriate activity of a RasGTPase may result from mutation or overexpression of Ras GTPase, forexample the G13D mutation in KRas2, and may lead to overactivation ofthe MAPK pathway mediated by Raf family kinase activity.

Thus, in one embodiment, the present invention provides compounds foruse in the treatment of a condition which directly or indirectly resultsfrom a mutation of a Raf family kinase or overexpression of a Raf familykinase, or a mutation of an upstream activator of a Raf family kinase oroverexpression of an upstream activator of a Raf family kinase in amammal in need thereof. The present invention provides methods for thetreatment of a condition which directly or indirectly results frommutation of a Raf family kinase or overexpression of a Raf familykinase, or a mutation of an upstream activator of a Raf family kinase oroverexpression of an upstream activator of a Raf family kinase in amammal in need thereof, comprising administering to the mammal, atherapeutically effective amount of a compound of the invention. In anadditional aspect, the present invention provides the use of a compoundof the invention for the preparation of a medicament for the treatmentof a condition which directly or indirectly results from mutation of aRaf family kinase or overexpression of a Raf family kinase, or amutation of an upstream activator of a Raf family kinase oroverexpression of an upstream activator of a Raf family kinase in amammal. Conditions which are mediated by at least one Raf family kinase,and particularly conditions mediated by inappropriate activity of one ormore Raf family kinases, including those which directly or indirectlyresult from mutation of a Raf family kinase, overexpression of a Raffamily kinase, or mutation of an upstream activator of a Raf familykinase or overexpression of an upstream activator of a Raf family kinaseare known in the art and include but are not limited to neoplasms.

Compounds of the invention may also be used in the treatment ofconditions attenuated by inhibition of a Raf family kinase (particularlyB-Raf). Further provided are methods for treating a condition attenuatedby inhibition of a Raf family kinase (particularly B-Raf) in a mammal inneed thereof, comprising administering to the mammal, a therapeuticallyeffective amount of a compound of the invention. Also provided is theuse of a compound of the invention for the preparation of a medicamentfor the treatment of a condition attenuated by inhibition of a Raffamily kinase (particularly B-Raf) in a mammal. Conditions attenuated byinhibition of a Raf family kinase (including B-Raf) include but are notlimited to neoplasms.

Accordingly, compounds of the invention may be used in the treatment ofa neoplasm, particularly a susceptible neoplasm (a cancer or tumor) in amammal. The present invention also provides a method for treating aneoplasm, particularly a susceptible neoplasm in a mammal in needthereof, which method comprises administering to the mammal atherapeutically effective amount of the compound of the invention. Theinvention also provides the use of a compound of the invention for thepreparation of a medicament for the treatment of neoplasm, particularlya susceptible neoplasm, in a mammal.

“Susceptible neoplasm” as used herein refers to neoplasms which aresusceptible to treatment by a kinase inhibitor and particularlyneoplasms that are susceptible to treatment by a Raf inhibitor.Neoplasms which have been associated with inappropriate activity of oneor more Raf family kinases and particularly neoplasms which are exhibitmutation of a Raf family kinase, overexpression of a Raf family kinase,or mutation of an upstream activator of a Raf family kinase oroverexpression of an upstream activator of a Raf family kinase, and aretherefore susceptible to treatment with an Raf inhibitor are known inthe art, and include both primary and metastatic tumors and cancers.See, Catalogue of Somatic Mutations in Cancer (COSMIC), the WellcomeTrust Sanger Institute, http://www.sanger.ac.uk/genetics/CGP/cosmic/ andthose references cited in the background.

Specific examples of susceptible neoplasms within the scope of theinvention include, but are not limited to:

-   Barret's adenocarcinoma;-   billiary tract carcinomas;-   breast cancer;-   cervical cancer;-   cholangiocarcinoma;-   central nervous system tumors including primary CNS tumors such as    glioblastomas, astrocytomas (including glioblastoma multiforme) and    ependymomas, and secondary CNS tumors (i.e., metastases to the    central nervous system of tumors originating outside of the central    nervous system),-   colorectal cancer, including large intestinal colon carcinoma;-   gastric cancer;-   carcinoma of the head and neck including squamous cell carcinoma of    the head and neck;-   hematologic cancers including leukemias and lymphomas such as acute    lymphoblastic leukemia, acute myelogenous leukemia (AML),    myelodysplastic syndromes, chronic myelogenous leukemia, Hodgkin's    lymphoma, non-Hodgkin's lymphoma, megakaryoblastic leukemia,    multiple myeloma and erythroleukemia;-   hepatocellular carcinoma;-   lung cancer including small cell lung cancer and non-small cell lung    cancer;-   ovarian cancer;-   endometrial cancer;-   pancreatic cancer;-   pituitary adenoma;-   prostate cancer;-   renal cancer;-   sarcoma;-   skin cancers including melanomas; and-   thyroid cancers.

The foregoing list is intended to disclose each of the recited neoplasmsindividually. In one particular embodiment, the susceptible neoplasm isa neoplasm which exhibits a mutation in BRaf.

Accordingly, in one embodiment, the present invention provides a methodfor the treatment of any of Barret's adenocarcinoma; billiary tractcarcinomas; breast cancer; cervical cancer; cholangiocarcinoma; centralnervous system tumors including primary CNS tumors such asglioblastomas, astrocytomas (e.g., glioblastoma multiforme) andependymomas, and secondary CNS tumors (i.e., metastases to the centralnervous system of tumors originating outside of the central nervoussystem); colorectal cancer including large intestinal colon carcinoma;gastric cancer; carcinoma of the head and neck including squamous cellcarcinoma of the head and neck; hematologic cancers including leukemiasand lymphomas such as acute lymphoblastic leukemia, acute myelogenousleukemia (AML), myelodysplastic syndromes, chronic myelogenous leukemia,Hodgkin's lymphoma, non-Hodgkin's lymphoma, megakaryoblastic leukemia,multiple myeloma and erythroleukemia; hepatocellular carcinoma; lungcancer including small cell lung cancer and non-small cell lung cancer;ovarian cancer; endometrial cancer; pancreatic cancer; pituitaryadenoma; prostate cancer; renal cancer; sarcoma; skin cancers includingmelanomas; and thyroid cancers, or any subset thereof, in a mammal(e.g., human) in need thereof. The method comprises administering atherapeutically effective amount of a compound of the invention to themammal (e.g., human).

In one embodiment, the present invention provides a method for treatingbreast cancer, cholangiocarcinoma, colorectal cancer, melanoma,non-small cell lung cancer, ovarian cancer, or thyroid cancer, or anysubset thereof.

In one particular embodiment, the present invention provides a methodfor treating cholangiocarcinoma, colorectal cancer, melanoma, or thyroidcancer, or any subset thereof.

In one preferred embodiment, the present invention provides a method fortreating colorectal cancer in a mammal (e.g., human) in need thereof.The method comprises administering to the mammal (e.g. human) atherapeutically effective amount of a compound of formula (I). In onepreferred embodiment, the compound is selected from

-   N-{3-[5-(2-amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide;-   N-{3-[2-(1,1-dimethylethyl)-5-(2-methyl-4-pyrimidinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide;-   N-{3-[5-(2-amino-4-pyrimidinyl)-2-(tetrahydro-2H-pyran-4-yl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide;-   N-{3-[5-(2-amino-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide;-   N-{3-[5-(2-amino-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]-2-chlorophenyl}-2-furansulfonamide;-   N-{3-[5-(2-amino-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]-2-chlorophenyl}-2,5-difluorobenzenesulfonamide;    and-   N-{3-[2-(1,1-dimethylethyl)-5-(4-pyrimidinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide;    and pharmaceutically acceptable salts thereof. In one particular    embodiment, the method comprises administering    N-{3-[5-(2-amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide    in the form of either a free base or a pharmaceutically acceptable    salt thereof. In another particular embodiment, the method comprises    administering    N-{3-[2-(1,1-dimethylethyl)-5-(2-methyl-4-pyrimidinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide    in the form of either a free base or a pharmaceutically acceptable    salt thereof. In another particular embodiment, the method comprises    administering    N-{3-[5-(2-amino-4-pyrimidinyl)-2-(tetrahydro-2H-pyran-4-yl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide    in the form of either a free base or a pharmaceutically acceptable    salt thereof.

In one preferred embodiment, the present invention provides a method fortreating melanoma in a mammal (e.g., human) in need thereof. The methodcomprises administering to the mammal (e.g. human) a therapeuticallyeffective amount of a compound of formula (I). In one preferredembodiment, the compound is selected from

-   N-{3-[5-(2-amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide;-   N-{3-[2-(1,1-dimethylethyl)-5-(2-methyl-4-pyrimidinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide;-   N-{3-[5-(2-amino-4-pyrimidinyl)-2-(tetrahydro-2H-pyran-4-yl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide;-   N-{3-[5-(2-amino-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide;-   N-{3-[5-(2-amino-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]-2-chlorophenyl}-2-furansulfonamide;-   N-{3-[5-(2-amino-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]-2-chlorophenyl}-2,5-difluorobenzenesulfonamide;    and-   N-{3-[2-(1,1-dimethylethyl)-5-(4-pyrimidinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide;    and pharmaceutically acceptable salts thereof. In one particular    embodiment, the method comprises administering    N-{3-[5-(2-amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide    in the form of either a free base or a pharmaceutically acceptable    salt thereof. In another particular embodiment, the method comprises    administering    N-{3-[2-(1,1-dimethylethyl)-5-(2-methyl-4-pyrimidinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide    in the form of either a free base or a pharmaceutically acceptable    salt thereof. In another particular embodiment, the method comprises    administering    N-{3-[5-(2-amino-4-pyrimidinyl)-2-(tetrahydro-2H-pyran-4-yl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide    in the form of either a free base or a pharmaceutically acceptable    salt thereof.

In one preferred embodiment, the present invention provides a method fortreating cholangiocarcinoma in a mammal (e.g., human) in need thereof.The method comprises administering to the mammal (e.g. human) atherapeutically effective amount of a compound of formula (I). In onepreferred embodiment, the compound is selected from

-   N-{3-[5-(2-amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide;-   N-{3-[2-(1,1-dimethylethyl)-5-(2-methyl-4-pyrimidinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide;-   N-{3-[5-(2-amino-4-pyrimidinyl)-2-(tetrahydro-2H-pyran-4-yl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide;-   N-{3-[5-(2-amino-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide;-   N-{3-[5-(2-amino-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]-2-chlorophenyl}-2-furansulfonamide;-   N-{3-[5-(2-amino-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]-2-chlorophenyl}-2,5-difluorobenzenesulfonamide;    and-   N-{3-[2-(1,1-dimethylethyl)-5-(4-pyrimidinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide;    and pharmaceutically acceptable salts thereof. In one particular    embodiment, the method comprises administering    N-{3-[5-(2-amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide    in the form of either a free base or a pharmaceutically acceptable    salt thereof. In another particular embodiment, the method comprises    administering    N-{3-[2-(1,1-dimethylethyl)-5-(2-methyl-4-pyrimidinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide    in the form of either a free base or a pharmaceutically acceptable    salt thereof. In another particular embodiment, the method comprises    administering    N-{3-[5-(2-amino-4-pyrimidinyl)-2-(tetrahydro-2H-pyran-4-yl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide    in the form of either a free base or a pharmaceutically acceptable    salt thereof.

In one preferred embodiment, the present invention provides a method fortreating thyroid cancer in a mammal (e.g., human) in need thereof. Themethod comprises administering to the mammal (e.g. human) atherapeutically effective amount of a compound of formula (I). In onepreferred embodiment, the compound is selected from

-   N-{3-[5-(2-amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide;-   N-{3-[2-(1,1-dimethylethyl)-5-(2-methyl-4-pyrimidinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide;-   N-{3-[5-(2-amino-4-pyrimidinyl)-2-(tetrahydro-2H-pyran-4-yl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide;-   N-{3-[5-(2-amino-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide;-   N-{3-[5-(2-amino-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]-2-chlorophenyl}-2-furansulfonamide;-   N-{3-[5-(2-amino-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]-2-chlorophenyl}-2,5-difluorobenzenesulfonamide;    and-   N-{3-[2-(1,1-dimethylethyl)-5-(4-pyrimidinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide;    and pharmaceutically acceptable salts thereof. In one particular    embodiment, the method comprises administering    N-{3-[5-(2-amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide    in the form of either a free base or a pharmaceutically acceptable    salt thereof. In another particular embodiment, the method comprises    administering    N-{3-[2-(1,1-dimethylethyl)-5-(2-methyl-4-pyrimidinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide    in the form of either a free base or a pharmaceutically acceptable    salt thereof. In another particular embodiment, the method comprises    administering    N-{3-[5-(2-amino-4-pyrimidinyl)-2-(tetrahydro-2H-pyran-4-yl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide    in the form of either a free base or a pharmaceutically acceptable    salt thereof.

In one preferred embodiment, the present invention provides a method fortreating breast cancer in a mammal (e.g., human) in need thereof. Themethod comprises administering to the mammal (e.g. human) atherapeutically effective amount of a compound of formula (I). In onepreferred embodiment, the compound is selected from

-   N-{3-[5-(2-amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide;-   N-{3-[2-(1,1-dimethylethyl)-5-(2-methyl-4-pyrimidinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide;-   N-{3-[5-(2-amino-4-pyrimidinyl)-2-(tetrahydro-2H-pyran-4-yl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide;-   N-{3-[5-(2-amino-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide;-   N-{3-[5-(2-amino-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]-2-chlorophenyl}-2-furansulfonamide;-   N-{3-[5-(2-amino-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]-2-chlorophenyl}-2,5-difluorobenzenesulfonamide;    and-   N-{3-[2-(1,1-dimethylethyl)-5-(4-pyrimidinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide;    and pharmaceutically acceptable salts thereof. In one particular    embodiment, the method comprises administering    N-{3-[5-(2-amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide    in the form of either a free base or a pharmaceutically acceptable    salt thereof. In another particular embodiment, the method comprises    administering    N-{3-[2-(1,1-dimethylethyl)-5-(2-methyl-4-pyrimidinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide    in the form of either a free base or a pharmaceutically acceptable    salt thereof. In another particular embodiment, the method comprises    administering    N-{3-[5-(2-amino-4-pyrimidinyl)-2-(tetrahydro-2H-pyran-4-yl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide    in the form of either a free base or a pharmaceutically acceptable    salt thereof.

In one preferred embodiment, the present invention provides a method fortreating ovarian cancer in a mammal (e.g., human) in need thereof. Themethod comprises administering to the mammal (e.g. human) atherapeutically effective amount of a compound of formula (I). In onepreferred embodiment, the compound is selected from

-   N-{3-[5-(2-amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide;-   N-{3-[2-(1,1-dimethylethyl)-5-(2-methyl-4-pyrimidinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide;-   N-{3-[5-(2-amino-4-pyrimidinyl)-2-(tetrahydro-2H-pyran-4-yl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide;-   N-{3-[5-(2-amino-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide;-   N-{3-[5-(2-amino-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]-2-chlorophenyl}-2-furansulfonamide;-   N-{3-[5-(2-amino-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]-2-chlorophenyl}-2,5-difluorobenzenesulfonamide;    and-   N-{3-[2-(1,1-dimethylethyl)-5-(4-pyrimidinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide;    and pharmaceutically acceptable salts thereof. In one particular    embodiment, the method comprises administering    N-{3-[5-(2-amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide    in the form of either a free base or a pharmaceutically acceptable    salt thereof. In another particular embodiment, the method comprises    administering    N-{3-[2-(1,1-dimethylethyl)-5-(2-methyl-4-pyrimidinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide    in the form of either a free base or a pharmaceutically acceptable    salt thereof. In another particular embodiment, the method comprises    administering    N-{3-[5-(2-amino-4-pyrimidinyl)-2-(tetrahydro-2H-pyran-4-yl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide    in the form of either a free base or a pharmaceutically acceptable    salt thereof.

In one preferred embodiment, the present invention provides a method fortreating non-small cell lung cancer in a mammal (e.g., human) in needthereof. The method comprises administering to the mammal (e.g. human) atherapeutically effective amount of a compound of formula (I). In onepreferred embodiment, the compound is selected from

-   N-{3-[5-(2-amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide;-   N-{3-[2-(1,1-dimethylethyl)-5-(2-methyl-4-pyrimidinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide;-   N-{3-[5-(2-amino-4-pyrimidinyl)-2-(tetrahydro-2H-pyran-4-yl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide;-   N-{3-[5-(2-amino-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide;-   N-{3-[5-(2-amino-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]-2-chlorophenyl}-2-furansulfonamide;    and-   N-{3-[5-(2-amino-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]-2-chlorophenyl}-2,5-difluorobenzenesulfonamide;    and-   N-{3-[2-(1,1-dimethylethyl)-5-(4-pyrimidinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide;    and pharmaceutically acceptable salts thereof. In one particular    embodiment, the method comprises administering    N-{3-[5-(2-amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide    in the form of either a free base or a pharmaceutically acceptable    salt thereof. In another particular embodiment, the method comprises    administering    N-{3-[2-(1,1-dimethylethyl)-5-(2-methyl-4-pyrimidinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide    in the form of either a free base or a pharmaceutically acceptable    salt thereof. In another particular embodiment, the method comprises    administering    N-{3-[5-(2-amino-4-pyrimidinyl)-2-(tetrahydro-2H-pyran-4-yl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide    in the form of either a free base or a pharmaceutically acceptable    salt thereof.

The present invention also provides the a compound of formula (I) foruse in the treatment of Barret's adenocarcinoma; billiary tractcarcinomas; breast cancer; cervical cancer; cholangiocarcinoma; centralnervous system tumors including primary CNS tumors such asglioblastomas, astrocytomas (e.g., glioblastoma multiforme) andependymomas, and secondary CNS tumors (i.e., metastases to the centralnervous system of tumors originating outside of the central nervoussystem); colorectal cancer including large intestinal colon carcinoma;gastric cancer; carcinoma of the head and neck including squamous cellcarcinoma of the head and neck; hematologic cancers including leukemiasand lymphomas such as acute lymphoblastic leukemia, acute myelogenousleukemia (AML), myelodysplastic syndromes, chronic myelogenous leukemia,Hodgkin's lymphoma, non-Hodgkin's lymphoma, megakaryoblastic leukemia,multiple myeloma and erythroleukemia; hepatocellular carcinoma; lungcancer including small cell lung cancer and non-small cell lung cancer;ovarian cancer; endometrial cancer; pancreatic cancer; pituitaryadenoma; prostate cancer; renal cancer; sarcoma; skin cancers includingmelanomas; and thyroid cancers, or any subset thereof, in a mammal(e.g., human).

The present invention further provides the use of a compound of formula(I) for the preparation of a medicament for the treatment of Barret'sadenocarcinoma; billiary tract carcinomas; breast cancer; cervicalcancer; cholangiocarcinoma; central nervous system tumors includingprimary CNS tumors such as glioblastomas, astrocytomas (e.g.,glioblastoma multiforme) and ependymomas, and secondary CNS tumors(i.e., metastases to the central nervous system of tumors originatingoutside of the central nervous system); colorectal cancer includinglarge intestinal colon carcinoma; gastric cancer; carcinoma of the headand neck including squamous cell carcinoma of the head and neck;hematologic cancers including leukemias and lymphomas such as acutelymphoblastic leukemia, acute myelogenous leukemia (AML),myelodysplastic syndromes, chronic myelogenous leukemia, Hodgkin'slymphoma, non-Hodgkin's lymphoma, megakaryoblastic leukemia, multiplemyeloma and erythroleukemia; hepatocellular carcinoma; lung cancerincluding small cell lung cancer and non-small cell lung cancer; ovariancancer; endometrial cancer; pancreatic cancer; pituitary adenoma;prostate cancer; renal cancer; sarcoma; skin cancers includingmelanomas; and thyroid cancers, or any subset thereof, in a mammal(e.g., human).

As is well known in the art, tumors may metastasize from a first orprimary locus of tumor to one or more other body tissues or sites. Inparticular, metastases to the central nervous system (i.e., secondaryCNS tumors), and particularly the brain (i.e., brain metastases), arewell documented for tumors and cancers, such as breast, lung, melanoma,renal and colorectal. As used herein, reference to uses or methods fortreatment or treatments for a “neoplasm,” “tumor” or “cancer” in asubject includes use for and treatment of the primary neoplasm, tumor orcancer, and where appropriate, also the use for and treatment ofmetastases (i.e., metastatic tumor growth) as well.

In another embodiment, the susceptible neoplasm is colorectal cancer andthe invention provides compounds for use in the treatment of colorectalcancer in a mammal (e.g., human) and the use of such compounds for thepreparation of a medicament for the treatment of colorectal cancer in amammal (e.g., human).

In another embodiment, the susceptible neoplasm is melanoma, and theinvention provides compounds for use in the treatment of melanoma in amammal (e.g., human) and the use of such compounds for the preparationof a medicament for the treatment of melanoma in a mammal (e.g., human).

In another embodiment, the susceptible neoplasm is cholangiocarcinoma,and the invention provides compounds for use in the treatment ofcholangiocarcinoma in a mammal (e.g., human) and the use of suchcompounds for the preparation of a medicament for the treatment ofcholangiocarcinoma in a mammal (e.g., human).

In another embodiment, the susceptible neoplasm is thyroid cancer, andthe invention provides compounds for use in the treatment of thyroidcancer in a mammal (e.g., human) and the use of such compounds for thepreparation of a medicament for the treatment of thyroid cancer in amammal (e.g., human).

In one particular embodiment, the susceptible neoplasm is breast cancerand the invention provides compounds for use in the treatment of breastcancer in a mammal (e.g., human) and the use of such compounds for thepreparation of a medicament for the treatment of breast cancer in amammal (e.g., human).

In another embodiment, the susceptible neoplasm is ovarian cancer andthe invention provides compounds for use in the treatment of ovariancancer in a mammal (e.g., human) and the use of such compounds for thepreparation of a medicament for the treatment of ovarian cancer in amammal (e.g., human).

In another embodiment, the susceptible neoplasm is non-small cell lungcancer, and the invention provides compounds for use in the treatment ofnon-small cell lung cancer in a mammal (e.g., human) and the use of suchcompounds for the preparation of a medicament for the treatment ofnon-small cell lung cancer in a mammal (e.g., human).

The compounds of the invention can be used alone in the treatment ofeach of the foregoing conditions or can be used to provide additive orpotentially synergistic effects with certain existing chemotherapies,radiation, biological or immunotherapeutics (including monoclonalantibodies) and vaccines. The compounds of the invention may be usefulfor restoring effectiveness of certain existing chemotherapies andradiation and or increasing sensitivity to certain existingchemotherapies and/or radiation.

In addition to the treatment of susceptible neoplasms, the compounds ofthe invention may also be used in the treatment of other conditionsattenuated by inhibition of a Raf family kinase, such as cardio-faciocutaneous syndrome and polycystic kidney disease.

In one aspect, the present invention provides a method for treating asusceptible neoplasm in a mammal in need thereof comprising the stepsof:

-   -   (a) analyzing a sample from said neoplasm to determine whether        an activating mutation is present in the coding sequence for        B-Raf in cells of said neoplasm;    -   (b) selecting a mammal having a neoplasm with an activating        mutation in the coding sequence for B-Raf; and    -   (c) administering a therapeutically effective amount of a        compound of the present invention to the mammal selected in step        (b).

In certain embodiments, the activating mutation present in the codingsequence for BRAF results in a BRAF having an amino acid substitutionselected from the group consisting of R462I, I463S, G464V, G464E, G466A,G466E, G466V, G469A, G469E, D594V, F595L, G596R, L597V, L597R, T599I,V600E, V600D, V600K, V600R, T119S, and K601E. See, for example, FIG. 2of Halilovic and Solvit (2008) Current Opinion in Pharmacology 8:419-26.

In one embodiment, the present invention provides a method for treatinga susceptible neoplasm in a mammal in need thereof comprising the stepsof:

-   -   (a) analyzing a sample from said neoplasm to determine whether a        mutation encoding a V600E amino acid substitution is present in        the coding sequence for B-Raf in cells of said neoplasm;    -   (b) selecting a mammal having a neoplasm with a mutation        encoding the V600E amino acid substitution in B-Raf; and    -   (c) administering a therapeutically effective amount of a        compound of the present invention to the mammal selected in step        (b).

The V600E amino acid substitution in B-Raf is described, for example, inKumar et al. (2004) J Invest Dermatol. 122(2):342-8. This mutationcommonly results from a T1799A mutation in the coding sequence for humanB-Raf. Accordingly, in one embodiment of the present invention, the stepof analyzing a sample from said neoplasm to determine whether a mutationencoding a V600E amino acid substitution is present in the codingsequence for B-Raf is performed by determining whether the codingsequence for B-Raf in cells of the neoplasm contains the T1799Amutation.

The neoplasm may be selected from Barret's adenocarcinoma; billiarytract carcinomas; breast cancer; cervical cancer; cholangiocarcinoma;central nervous system tumors including primary CNS tumors such asglioblastomas, astrocytomas (e.g., glioblastoma multiforme) andependymomas, and secondary CNS tumors (i.e., metastases to the centralnervous system of tumors originating outside of the central nervoussystem); colorectal cancer including large intestinal colon carcinoma;gastric cancer; carcinoma of the head and neck including squamous cellcarcinoma of the head and neck; hematologic cancers including leukemiasand lymphomas such as acute lymphoblastic leukemia, acute myelogenousleukemia (AML), myelodysplastic syndromes, chronic myelogenous leukemia,Hodgkin's lymphoma, non-Hodgkin's lymphoma, megakaryoblastic leukemia,multiple myeloma and erythroleukemia; hepatocellular carcinoma; lungcancer including small cell lung cancer and non-small cell lung cancer;ovarian cancer; endometrial cancer; pancreatic cancer; pituitaryadenoma; prostate cancer; renal cancer; sarcoma; skin cancers includingmelanomas; and thyroid cancers.

In particular embodiments, the neoplasm is selected from breast cancer,cholangiocarcinoma, colorectal cancer, melanoma, non-small cell lungcancer, ovarian cancer, and thyroid cancer. In one preferred embodiment,the neoplasm is melanoma.

In one embodiment, the mammal is a human.

In one embodiment, the compound of the invention is,N-{3-[5-(2-amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamideor a pharmaceutically acceptable salt thereof. In a particularembodiment, the compound of the invention isN-{3-[5-(2-amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamidemesylate. In an alternate embodiment, the compound of the invention isN-{3-[5-(2-amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide

The sample of the neoplasm to be analyzed for the presence of B-rafactivating mutations can be derived from a variety of sources including,but not limited to, single cells, a collection of cells, tissue, cellculture, bone marrow, blood, or other bodily fluids. The tissue or cellsource may include a tissue biopsy sample, a cell sorted population,cell culture, or a single cell. In selecting a sample, the percentage ofthe sample that constitutes neoplastic cells should be considered. Insome embodiments, the sample from the neoplasm is fixed using apreservative prior to analyzing for the presence of an activatingmutation.

The step of analyzing a sample from the neoplasm to determine whether anactivating mutation is present in the coding sequence for B-Raf in cellsof said neoplasm may be performed using any method known in the art. Forexample, the coding sequence for B-raf in cells of the sample may beanalyzed to determine if it contains a mutation which results in theexpression of activated B-Raf. Methods for detecting such mutations arewell known in the art. See, for example, Whitcombe et al. (1999) NatureBiotechnology 17:804-7, Gibson (2006) Clinica Chimica Acta 363: 32-47,Kim and Misra (2007) Annual Review of Biomedical Engineering 9:289-320,and U.S. Pat. Nos. 6,326,145 and 6,270,967). Alternatively, activatingmutations in B-Raf may be identified by directly detecting the activatedB-raf protein using an agent (e.g. an antibody) that selectively bindsactivated B-raf.

As used herein, the term “therapeutically effective amount” means anamount of a compound of the invention which is sufficient, in thesubject to which it is administered, to elicit a biological or medicalresponse of a cell culture, tissue, system, mammal (including human)that is being sought, for instance, by a researcher or clinician. Theterm also includes within its scope amounts effective to enhance normalphysiological function. For example, a therapeutically effective amountof a compound of the invention for the treatment of a condition mediatedby at least one Raf family kinase is an amount sufficient to treat thecondition in the particular subject. Similarly, a therapeuticallyeffective amount of a compound of the invention for the treatment of asusceptible neoplasm is an amount sufficient to treat the particularsusceptible neoplasm in the subject. In one embodiment of the presentinvention, a therapeutically effective amount of a compound of theinvention is an amount sufficient to regulate, modulate, bind or inhibitat least one Raf family kinase. More particularly, in such embodiment,the therapeutically effective amount of a compound of the invention isan amount sufficient to regulate, modulate, bind or inhibit B-Raf.

The precise therapeutically effective amount of the compounds of theinvention will depend on a number of factors. There are variablesinherent to the compounds including, but not limited to, the following:molecular weight, inhibitory activity at the target kinase, absorption,bioavailability, distribution in the body, tissue penetration,half-life, metabolism, protein binding, and excretion. These variablesdetermine what dose of compound needs to be administered in order toinhibit the target kinase by a sufficient percentage and for asufficient amount of time to have the desired effect on the conditionbeing treated (e.g., neoplasm). In general, the goal will be to inhibitthe target kinase by 50% or more for as long as possible. The durationof drug exposure will be limited only by the compound half-life, andside effects from treatment requiring cessation of dosing. The amount ofcompound administered will also depend on factors related to patientsand disease including, but not limited to, the following: the age,weight, concomitant medications and medical condition of the subjectbeing treated, the precise condition requiring treatment and itsseverity, the nature of the formulation, and the route ofadministration. Ultimately the dose will be at the discretion of theattendant physician or veterinarian. Typically, the compound of theinvention will be given for treatment in the range of 0.01 to 30 mg/kgbody weight of recipient (mammal) per day or per dose or per cycle oftreatment and more usually in the range of 0.1 to 10 mg/kg body weightper day or per dose or per cycle of treatment. Thus, for a 70 kg adulthuman being treated for a condition mediated by or correlated to atleast one Raf family kinase, the actual amount per day or per dose orper cycle of treatment would usually be from 1 to 2000 mg and thisamount may be given in a single or multiple doses per day or per dose orper cycle of treatment. Dosing regimens may vary significantly and willbe determined and altered based on clinical experience with thecompound. The full spectrum of dosing regimens may be employed rangingfrom continuous dosing (with daily doses) to intermittent dosing. Atherapeutically effective amount of a pharmaceutically acceptable saltof a compound of formula (I) may be determined as a proportion of thetherapeutically effective amount of the compound of formula (I) as thefree base. It is envisaged that similar dosages would be appropriate fortreatment of the susceptible neoplasms described above.

While it is possible that, for use in therapy, a therapeuticallyeffective amount of a compound of the invention may be administered asthe raw chemical, it is typically presented as the active ingredient ofa pharmaceutical composition or formulation. Accordingly, the inventionfurther provides a pharmaceutical composition comprising a compound ofthe invention. The pharmaceutical composition may further comprise oneor more pharmaceutically acceptable carriers, diluents, and/orexcipients. The carrier(s), diluent(s) and/or excipient(s) must beacceptable in the sense of being compatible with the other ingredientsof the formulation and not deleterious to the recipient thereof. Inaccordance with another aspect of the invention there is also provided aprocess for the preparation of a pharmaceutical formulation includingadmixing a compound of the invention with one or more pharmaceuticallyacceptable carriers, diluents and/or excipients.

Pharmaceutical formulations may be presented in unit dose formscontaining a predetermined amount of active ingredient per unit dose.Such a unit may contain, for example, 0.5 mg to 1 g, preferably 1 mg to700 mg, more preferably 5 mg to 100 mg of a compound of the invention(as a free-base, solvate (including hydrate) or salt, in any form),depending on the condition being treated, the route of administration,and the age, weight and condition of the patient. Preferred unit dosageformulations are those containing a daily dose, weekly dose, monthlydose, a sub-dose or an appropriate fraction thereof, of an activeingredient. Furthermore, such pharmaceutical formulations may beprepared by any of the methods well known in the pharmacy art.

Pharmaceutical formulations may be adapted for administration by anyappropriate route, for example by the oral (including capsules, tablets,liquid-filled capsules, disintegrating tablets, immediate, delayed andcontrolled release tablets, oral strips, solutions, syrups, buccal andsublingual), rectal, nasal, inhalation, topical (including transdermal),vaginal or parenteral (including subcutaneous, intramuscular,intravenous or intradermal) route. Such formulations may be prepared byany method known in the art of pharmacy, for example by bringing intoassociation the active ingredient with the carrier(s), excipient(s) ordiluent. Generally, the carrier, excipient or diluent employed in thepharmaceutical formulation is “non-toxic,” meaning that it/they is/aredeemed safe for consumption in the amount delivered in thepharmaceutical composition, and “inert” meaning that it/they does/do notappreciably react with or result in an undesired effect on thetherapeutic activity of the active ingredient.

Pharmaceutical formulations adapted for oral administration may bepresented as discrete units such as liquid-filled or solid capsules;immediate, delayed or controlled release tablets; powders or granules;solutions or suspensions in aqueous or non-aqueous liquids; edible foamsor whips; oil-in-water liquid emulsions, water-in-oil liquid emulsionsor oral strips, such as impregnated gel strips.

For instance, for oral administration in the form of a tablet orcapsule, the active drug component can be combined with an oralpharmaceutically acceptable carrier such as ethanol, glycerol, water andthe like. Powders are prepared by comminuting the compound to a suitablefine size and mixing with a similarly comminuted pharmaceutical carriersuch as an edible carbohydrate, as, for example, starch or mannitol.Flavoring, preservative, dispersing and coloring agent can also bepresent.

Solid capsules are made by preparing a powder mixture, as describedabove, and filling formed gelatin sheaths. Glidants and lubricants suchas colloidal silica, talc, magnesium stearate, calcium stearate or solidpolyethylene glycol can be added to the powder mixture before thefilling operation. A disintegrating or solubilizing agent such asagar-agar, calcium carbonate or sodium carbonate can also be added toimprove the availability of the medicament when the capsule is ingested.

Moreover, when desired or necessary, suitable binders, lubricants,disintegrating agents and coloring agents can also be incorporated intothe mixture. Suitable binders include starch, gelatin, natural sugarssuch as glucose or beta-lactose, corn sweeteners, natural and syntheticgums such as acacia, tragacanth or sodium alginate,carboxymethylcellulose, polyethylene glycol, waxes and the like.Lubricants used in these dosage forms include sodium oleate, sodiumstearate, magnesium stearate, sodium benzoate, sodium acetate, sodiumchloride and the like. Disintegrators include, without limitation,starch, methyl cellulose, agar, bentonite, xanthan gum and the like.Tablets are formulated, for example, by preparing a powder mixture,granulating or slugging, adding a lubricant and disintegrant andpressing into tablets. A powder mixture is prepared by mixing thecompound, suitably comminuted, with a diluent or base as describedabove, and optionally, with a binder such as carboxymethylcellulose, analginate, gelatin, or polyvinyl pyrrolidone, a solution retardant suchas paraffin, a resorption accelerator such as a quaternary salt and/oran absorption agent such as bentonite, kaolin or dicalcium phosphate.The powder mixture can be granulated by wetting with a binder such assyrup, starch paste, acadia mucilage or solutions of cellulosic orpolymeric materials and forcing through a screen. As an alternative togranulating, the powder mixture can be run through the tablet machineand the result is imperfectly formed slugs broken into granules. Thegranules can be lubricated to prevent sticking to the tablet formingdies by means of the addition of stearic acid, a stearate salt, talc ormineral oil. The lubricated mixture is then compressed into tablets. Thecompounds of the present invention can also be combined with a freeflowing inert carrier and compressed into tablets directly without goingthrough the granulating or slugging steps. A clear or opaque protectivecoating consisting of a sealing coat of shellac, a coating of sugar orpolymeric material and a polish coating of wax can be provided.Dyestuffs can be added to these coatings to distinguish different unitdosages.

Oral fluids such as solutions, syrups and elixirs can be prepared indosage unit form so that a given quantity contains a predeterminedamount of the compound. Solutions and syrups can be prepared bydissolving the compound in a suitably flavored aqueous solution, whileelixirs are prepared through the use of a pharmaceutically acceptablealcoholic vehicle. Suspensions can be formulated by dispersing thecompound in a pharmaceutically acceptable vehicle. Solubilizers andemulsifiers such as ethoxylated isostearyl alcohols and polyoxy ethylenesorbitol ethers, preservatives, flavor additive such as peppermint oilor natural sweeteners or saccharin or other artificial sweeteners, andthe like can also be added.

Where appropriate, unit dosage formulations for oral administration canbe microencapsulated. The formulation can also be prepared to prolong orsustain the release as for example by coating or embedding particulatematerial in polymers, wax or the like.

The compounds of the invention can also be administered in the form ofliposome delivery systems, such as small unilamellar vesicles, largeunilamellar vesicles and multilamellar vesicles. Liposomes can be formedfrom a variety of phospholipids, such as cholesterol, stearylamine orphosphatidylcholines.

The compounds of the invention may also be delivered by the use ofmonoclonal antibodies as individual carriers to which the compoundmolecules are coupled. The compounds may also be coupled with solublepolymers as targetable drug carriers. Such polymers can includepolyvinylpyrrolidone, pyran copolymer,polyhydroxypropyl-methacrylamidephenol,polyhydroxyethylaspartamidephenol, or polyethyleneoxide-polylysinesubstituted with palmitoyl residues. Furthermore, the compounds may becoupled to a class of biodegradable polymers useful in achievingcontrolled release of a drug, for example, polycentric acid, polepsiloncaprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals,polydihydropyrans, polycyanoacrylates and cross-linked or amphipathicblock copolymers of hydrogels.

Pharmaceutical formulations adapted for transdermal administration maybe presented as discrete patches intended to remain in intimate contactwith the epidermis of the recipient for a prolonged period of time. Forexample, the active ingredient may be delivered from the patch byiontophoresis as generally described in Pharmaceutical Research (1986)3(6):318.

Pharmaceutical formulations adapted for topical administration may beformulated as ointments, creams, suspensions, lotions, powders,solutions, pastes, gels, sprays, aerosols or oils. For treatments ofexternal tissues, such as skin, the formulations may be applied as atopical ointment or cream. When formulated in an ointment, the activeingredient may be employed with either a paraffinic or a water-miscibleointment base. Alternatively, the active ingredient may be formulated ina cream with an oil-in-water cream base or a water-in-oil base.Pharmaceutical formulations adapted for topical administrations to theeye include eye drops wherein the active ingredient is dissolved orsuspended in a suitable carrier, especially an aqueous solvent.Pharmaceutical formulations adapted for topical administration in themouth include lozenges, pastilles and mouth washes.

Pharmaceutical formulations adapted for rectal administration may bepresented as suppositories or as enemas.

Pharmaceutical formulations adapted for nasal administration wherein thecarrier is a solid include a coarse powder having a particle size forexample in the range 20 to 500 microns which is administered in themanner in which snuff is taken, i.e. by rapid inhalation through thenasal passage from a container of the powder held close up to the nose.Suitable formulations wherein the carrier is a liquid, foradministration as a nasal spray or as nasal drops, include aqueous oroil solutions of the active ingredient.

Pharmaceutical formulations adapted for administration by inhalationinclude fine particle dusts or mists, which may be generated by means ofvarious types of metered dose pressurized aerosols, metered doseinhalers, dry powder inhalers, nebulizers or insufflators.

Pharmaceutical formulations adapted for vaginal administration may bepresented as pessaries, tampons, creams, gels, pastes, foams or sprayformulations.

Pharmaceutical formulations adapted for parenteral administrationinclude aqueous and non-aqueous sterile injection solutions which maycontain anti-oxidants, buffers, bacteriostats and solutes which renderthe formulation of pharmaceutically acceptable tonicity with the bloodof the intended recipient; and aqueous and non-aqueous sterilesuspensions which may include suspending agents and thickening agents.The formulations may be presented in unit-dose or multi-dose containers,for example sealed ampoules and vials, and may be stored in afreeze-dried (lyophilized) condition requiring only the addition of thesterile liquid carrier, for example water for injection, immediatelyprior to use. Extemporaneous injection solutions and suspensions may beprepared from sterile powders, granules and tablets.

It should be understood that in addition to the ingredients particularlymentioned above, the formulations may include other agents conventionalin the art having regard to the type of formulation in question, forexample those suitable for oral administration may include flavoringagents.

In the above-described methods of treatment and uses, a compound of theinvention may be employed alone, in combination with one or more othercompounds of the invention or in combination with other therapeuticmethods or agents. In particular, in methods of treating a conditionattenuated by inhibition of at least one Raf family kinase and inmethods of treating susceptible neoplasms, combination with otherchemotherapeutic, biologic, hormonal, antibody and supportive careagents is envisaged as well as combination with surgical therapy andradiotherapy. Supportive care agents include analgesics, anti-emeticsand agents used to treat heamatologic side effects such as neutropenia.Analgesics are well known in the art. Anti-emetics include but are notlimited to 5HT₃ antagonists such as ondansetron, granisetron,dolasetron, palonosetron and the like; prochlorperazine; metaclopromide;diphenhydramine; promethazine; dexamethasone; lorazepam; haloperidol;dronabinol; olanzapine; and neurokinin-1 antagonists such as aprepitant,fosaprepitant and casopitant administered alone or in variouscombinations.

The term “chemotherapeutic” as used herein refers to any chemical agenthaving a therapeutic effect on the subject to which it is administered.“Chemotherapeutic” agents include but are not limited to anti-neoplasticagents. As used herein, “anti-neoplastic agents” include both cytotoxicand cytostatic agents including biological, immunological and vaccinetherapies. Combination therapies according to the invention thuscomprise the administration of at least one compound of the inventionand the use of at least one other treatment method. In one embodiment,combination therapies according to the invention comprise theadministration of at least one compound of the invention and surgicaltherapy. In one embodiment, combination therapies according to theinvention comprise the administration of at least one compound of theinvention and radiotherapy. In one embodiment, combination therapiesaccording to the invention comprise the administration of at least onecompound of the invention and at least one supportive care agent (e.g.,at least one anti-emetic agent). In one embodiment, combinationtherapies according to the present invention comprise the administrationof at least one compound of the invention and at least one otherchemotherapeutic agent. In one particular embodiment, the inventioncomprises the administration of at least one compound of the inventionand at least one anti-neoplastic agent.

As an additional aspect, the present invention provides the methods oftreatment and uses as described above, which comprise administering acompound of the invention together with at least one chemotherapeuticagent. In one particular embodiment, the chemotherapeutic agent is ananti-neoplastic agent. In another embodiment, the invention provides apharmaceutical composition as described above further comprising atleast one other chemotherapeutic agent, more particularly, thechemotherapeutic agent is an anti-neoplastic agent. The invention alsoprovides methods of treatment and uses as described above, whichcomprise administering a compound of the invention together with atleast one supportive care agent (e.g., anti-emetic agent).

The compounds of the invention and at least one additionalanti-neoplastic or supportive care therapy may be employed incombination concomitantly or sequentially in any therapeuticallyappropriate combination. The administration of a compound of theinvention with one or more other anti-neoplastic agents may be incombination in accordance with the invention by administrationconcomitantly in one unitary pharmaceutical composition including bothor all compounds or two or more separate pharmaceutical compositionseach including one or more of the compounds. The components of thecombination may be administered separately in a sequential mannerwherein one active ingredient is administered first and the other(s)second or vice versa. Such sequential administration may be close intime or remote in time.

When a compound of the invention is used in combination with ananti-neoplastic and/or supportive care agent, the dose of each compoundmay differ from that when the compound is used alone. Appropriate doseswill be readily appreciated by those skilled in the art. The appropriatedose of the compound(s) of the invention and the other therapeuticallyactive agent(s) and the relative timings of administration will beselected in order to achieve the desired combined therapeutic effect,and are within the expertise and discretion of the attendant clinician.

Typically, any chemotherapeutic agent that has activity against asusceptible neoplasm being treated may be utilized in combination withthe compounds of the invention, provided that the particular agent isclinically compatible with therapy employing a compound of theinvention. Typical anti-neoplastic agents useful in the presentinvention include, but are not limited to: alkylating agents,anti-metabolites, antitumor antibiotics, antimitotic agents,topoisomerase I and II inhibitors, hormones and hormonal analogues;retinoids, signal transduction pathway inhibitors including inhibitorsof cell growth or growth factor function, angiogenesis inhibitors, andserine/threonine or other kinase inhibitors; cyclin dependent kinaseinhibitors; antisense therapies and immunotherapeutic agents, includingmonoclonals, vaccines or other biological agents.

Alkylating agents are non-phase specific anti-neoplastic agents andstrong electrophiles. Typically, alkylating agents form covalentlinkages, by alkylation, to DNA through nucleophilic moieties of the DNAmolecule such as phosphate, amino, and hydroxyl groups. Such alkylationdisrupts nucleic acid function leading to cell death. Alkylating agentsmay be employed in combination with the compounds of the invention inthe compositions and methods described above. Examples of alkylatingagents include but are not limited to nitrogen mustards such ascyclophosphamides, temozolamide, melphalan, and chlorambucil;oxazaphosphor-ines; alkyl sulfonates such as busulfan; nitrosoureas suchas carmustine; triazenes such as dacarbazine; and platinum coordinationcomplexes such as cisplatin, oxaliplatin and carboplatin.

Antimetabolite neoplastic agents are phase specific anti-neoplasticagents that act at S phase (DNA synthesis) of the cell cycle byinhibiting DNA synthesis or by inhibiting purine or pyrimidine basesynthesis and thereby limiting DNA synthesis. The end result ofdiscontinuing S phase is cell death. Antimetabolite neoplastic agentsmay be employed in combination with the compounds of the invention inthe compositions and methods described above. Examples of antimetaboliteanti-neoplastic agents include but are not limited to purine andpyrimidine analogues and anti-folate compounds, and more specifically,hydroxyurea, cytosine, arabinoside, ralitrexed, tegafur, fluorouracil(e.g., 5FU), methotrexate, cytarabine, mercaptopurine and thioguanine.

Antitumor antibiotic agents are non-phase specific agents, which bind toor intercalate with DNA. Typically, such action disrupts ordinaryfunction of the nucleic acids, leading to cell death. Antitumorantibiotics may be employed in combination with the compounds of theinvention in the compositions and methods described above.

Examples of antitumor antibiotic agents include, but are not limited to,actinomycins such as dactinomycin; anthracyclines such as daunorubicin,doxorubicin, idarubicin, epirubicin and mitoxantrone; mitomycin C andbleomycins.

Antimicrotubule or antimitotic agents are phase specific agents activeagainst the microtubules of tumor cells during M or the mitosis phase ofthe cell cycle. Antimitotic agents may be employed in combination withthe compounds of the invention in the compositions and methods describedabove. Examples of antimitotic agents include, but are not limited to,diterpenoids, vinca alkaloids, polo-like kinase (Plk) inhibitors andCenpE inhibitors. Examples of diterpenoids include, but are not limitedto, paclitaxel and its analog docetaxel. Examples of vinca alkaloidsinclude, but are not limited to, vinblastine, vincristine, vindesine andvinorelbine. Plk inhibitors are discussed further below.

Topoisomerase inhibitors include inhibitors of Topoisomerase II andinhibitors of Topoisomerase I. Topoisomerase II inhibitors, such asepipodophyllotoxins, are anti-neoplastic agents derived from themandrake plant, that typically affect cells in the S and G₂ phases ofthe cell cycle by forming a ternary complex with topoisomerase II andDNA, causing DNA strand breaks. The strand breaks accumulate and celldeath follows. Examples of epipodophyllotoxins include, but are notlimited to, etoposide and teniposide. Camptothecins, includingcamptothecin and camptothecin derivatives, are available or underdevelopment as Topoisomerase I inhibitors. Examples of camptothecinsinclude, but are not limited to amsacrine, irinotecan, topotecan, andthe various optical forms of7-(4-methylpiperazino-methylene)-10,11-ethylenedioxy-20-camptothecin.Topoisomerase inhibitors may be employed in combination with thecompounds of the invention in the compositions and methods describedabove.

Hormones and hormonal analogues are useful compounds for treatingcancers in which there is a relationship between the hormone(s) andgrowth and/or lack of growth of the cancer. Antitumor hormones andhormonal analogues may be employed in combination with the compounds ofthe invention in the compositions and methods described above. Examplesof hormones and hormonal analogues believed to be useful in thetreatment of neoplasms include, but are not limited to antiestrogens,such as tamoxifen, toremifene, raloxifene, fulvestrant, iodoxyfene anddroloxifene; anti-androgens; such as flutamide, nilutamide, bicalutamideand cyproterone acetate; adrenocorticosteroids such as prednisone andprednisolone; aminoglutethimide and other aromatase inhibitors such asanastrozole, letrazole, vorazole, and exemestane; progestrins such asmegestrol acetate; 5α-reductase inhibitors such as finasteride anddutasteride; and gonadotropin-releasing hormones (GnRH) and analoguesthereof, such as Leutinizing Hormone-releasing Hormone (LHRH) agonistsand antagonists such as goserelin luprolide, leuprorelin and buserelin.

Retinoid(s) are compounds that bind to and activate at least oneretinoic acid receptor selected from RARα, RARβ, and RARγ and/orcompounds that bind to and activate at least one of RARα, RARβ, and RARγand also at least one retinoic X receptor (RXR), including RXRα, RXRβ,and RXRγ. Retinoids for use in the present invention typically haveaffinity for RAR, and particularly for RARα and/or RARβ. However,certain synthetic retinoids, such as 9-cis-retinoic acid also haveaffinity for both RAR and RXR. In one embodiment, the retinoid hasaffinity for RARα (and RARα agonist).

Examples of specific retinoids that may be used in combination with thecompounds of the invention include: retinoic acid; all-trans-retinoicacid (“ATRA” also known as “tretinoin”); tamibarotene (“Am80”);9-cis-retinoic acid((2E,4E,6Z,8E)-3,7-Dimethyl-9-(2,6,6-trimethylcyclohex-1-enyl)nona-2,4,6,8-tetraenoicAcid) (also known as “9-cis-Tretinoin”) (available from Sigma);Isotretinoin((2Z,4E,6E,8E)-3,7-dimethyl-9-(2,6,6-trimethyl-1-cyclohexenyl)nona-2,4,6,8-tetraenoicacid) (also known as “13-cis-retinoic acid”) (ACCUTANE®); Am580(4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphtamido)benzoic acid),See, M. Gianni, Blood 1996 87(4):1520-1531; TTNPB(4-[E-2-(5,6,7,8-Tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-1-propenyl]benzoicacid) (also known as “Ro 13-7410”) See, M. F. Boehm et al. J. Med. Chem.1994 37:2930 and R. P. Bissonnette et al., Mol. Cell. Biol. 199515:5576; and BMS753(4-[[(2,3-dihydro-1,1,3,3-tetramethyl-2-oxo-1H-inden-5-yl)carbonyl]amino]benzoicacid) See, U.S. Pat. No. 6,184,256. Other RARα agonists known the artmay also be used in the present invention.

Signal transduction pathway inhibitors are those inhibitors which blockor inhibit a chemical process which evokes an intracellular change. Asused herein these changes include, but are not limited to, cellproliferation or differentiation or survival. Signal transductionpathway inhibitors useful in the present invention include, but are notlimited to, inhibitors of receptor tyrosine kinases, non-receptortyrosine kinases, SH2/SH3 domain blockers, serine/threonine kinases,phosphatidyl inositol-3-OH kinases, myoinositol signaling, and Rasoncogenes. Signal transduction pathway inhibitors may be employed incombination with the compounds of the invention in the compositions andmethods described above.

Several protein tyrosine kinases catalyze the phosphorylation ofspecific tyrosine residues in various proteins involved in theregulation of cell growth. Such protein tyrosine kinases can be broadlyclassified as receptor or non-receptor kinases.

Receptor tyrosine kinase inhibitors which may be combined with thecompounds of the invention include those involved in the regulation ofcell growth, which receptor tyrosine kinases are sometimes referred toas “growth factor receptors.” Examples of growth factor receptorinhibitors, include but are not limited to inhibitors of: insulin growthfactor receptors (IGF-1R, IR and IRR); epidermal growth factor familyreceptors (EGFR, ErbB2, and ErbB4); platelet derived growth factorreceptors (PDGFRs), vascular endothelial growth factor receptors(VEGFRs), tyrosine kinase with immunoglobulin-like and epidermal growthfactor homology domains (TIE-2), macrophage colony stimulating factor(c-fms), c-kit, c-met, fibroblast growth factor receptors (FGFRs),hepatocyte growth factor receptors (HGFRs), Trk receptors (TrkA, TrkB,and TrkC), ephrin (Eph) receptors and the RET protooncogene.

Several inhibitors of growth factor receptors are under development andinclude ligand antagonists, antibodies, tyrosine kinase inhibitors,anti-sense oligonucleotides and aptamers. Any of these growth factorreceptor inhibitors may be employed in combination with the compounds ofthe invention in any of the compositions and methods/uses describedherein. Trastuzumab (Herceptin®) is an example of an anti-erbB2 antibodyinhibitor of growth factor function. One example of an anti-erbB1antibody inhibitor of growth factor function is cetuximab (Erbitux™,C225). Bevacizumab (Avastin®) is an example of a monoclonal antibodydirected against VEGFR. Examples of small molecule inhibitors ofepidermal growth factor receptors include but are not limited tolapatinib (Tykerb™) and erlotinib (TARCEVA®). Imatinib (GLEEVEC®) is oneexample of a PDGFR inhibitor. Examples of VEGFR inhibitors includepazopanib, ZD6474, AZD2171, PTK787, sunitinib and sorafenib.

In one embodiment, the invention provides methods of treatment of any ofthe various conditions enumerated above comprising administering acompound of the invention in combination with an EGFR or ErbB inhibitor.In one particular embodiment, the methods of the present inventioncomprise administering a compound of the invention in combination withlapatinib. In one particular embodiment, the methods of the presentinvention comprise administering a compound of the invention incombination with trastuzumab. In one particular embodiment, the methodsof the present invention comprise administering a compound of theinvention in combination with erlotinib. In one particular embodiment,the methods of the present invention comprise administering a compoundof the invention in combination with gefitinib.

In another embodiment, the present invention provides methods oftreatment of any of the various conditions enumerated above comprisingadministering a compound of the invention in combination with a VEGFRinhibitor. In one particular embodiment, the methods of the presentinvention comprise administering a compound of the invention incombination with pazopanib.

Tyrosine kinases that are not transmembrane growth factor receptorkinases are termed non-receptor, or intracellular tyrosine kinases.Inhibitors of non-receptor tyrosine kinases are sometimes referred to as“anti-metastatic agents” and are useful in the present invention.Targets or potential targets of anti-metastatic agents, include, but arenot limited to, c-Src, Lck, Fyn, Yes, Jak, Abl kinase (c-Abl andBcr-Abl), FAK (focal adhesion kinase) and Bruton's tyrosine kinase(BTK). Non-receptor kinases and agents, which inhibit non-receptortyrosine kinase function, are described in Sinha, S, and Corey, S. J.,(1999) J. Hematother. Stem Cell Res. 8:465-80; and Bolen, J. B. andBrugge, J. S., (1997) Annu. Rev. of Immunol. 15:371-404.

SH2/SH3 domain blockers are agents that disrupt SH2 or SH3 domainbinding in a variety of enzymes or adaptor proteins including, but notlimited to, PI3-K p85 subunit, Src family kinases, adaptor molecules(Shc, Crk, Nck, Grb2) and Ras-GAP. Examples of Src inhibitors include,but are not limited to, dasatinib and BMS-354825 (J. Med. Chem. (2004)47:6658-6661).

Inhibitors of serine/threonine kinases may also be used in combinationwith the compounds of the invention in any of the compositions andmethods described above. Examples of serine/threonine kinase inhibitorsthat may also be used in combination with a compound of the presentinvention include, but are not limited to, polo-like kinase inhibitors(Plk family e.g., Plk1, Plk2, and Plk3), which play critical roles inregulating processes in the cell cycle including the entry into and theexit from mitosis; MAP kinase cascade blockers, which include otherRas/Raf kinase inhibitors, mitogen or extracellular regulated kinases(MEKs), and extracellular regulated kinases (ERKs); Aurora kinaseinhibitors (including inhibitors of Aurora A and Aurora B); proteinkinase C (PKC) family member blockers, including inhibitors of PKCsubtypes (alpha, beta, gamma, epsilon, mu, lambda, iota, zeta);inhibitors of kappa-B (IkB) kinase family (IKK-alpha, IKK-beta); PKB/Aktkinase family inhibitors; and inhibitors of TGF-beta receptor kinases.Examples of Plk inhibitors are described in PCT Publication No.WO04/014899 and WO07/03036. Other examples of serine/threonine kinaseinhibitors are known in the art. In another embodiment, the presentinvention provides methods of treatment of any of the various conditionsenumerated above comprising administering a compound of the invention incombination with a Plk inhibitor. In one particular embodiment, themethods of the present invention comprise administering a compound ofthe invention in combination with5-{6-[(4-Methylpiperazin-1-yl)methyl]-1H-benzimidazol-1-yl}-3-{(1R)-1-[2-(trifluoromethyl)phenyl]ethoxy}thiophene-2-carboxamide.

Urokinase, also referred to as urokinase-type Plasminogen Activator(uPA), is a serine protease. Activation of the serine protease plasmintriggers a proteolysis cascade which is involved in thrombolysis orextracellular matrix degradation. Elevated expression of urokinase andseveral other components of the plasminogen activation system have beencorrelated with tumor malignancy including several aspects of cancerbiology such as cell adhesion, migration and cellular mitotic pathwaysas well. Inhibitors of urokinase expression may be used in combinationwith the compounds of the invention in the compositions and methodsdescribed above.

Inhibitors of Ras oncogene may also be useful in combination with thecompounds of the present invention. Such inhibitors include, but are notlimited to, inhibitors of farnesyltransferase, geranyl-geranyltransferase, and CAAX proteases as well as anti-sense oligonucleotides,ribozymes and immunotherapy. Such inhibitors have been shown to blockRas activation in cells containing mutant Ras, thereby acting asantiproliferative agents.

Inhibitors of kinases involved in the IGF-1R signaling axis may also beuseful in combination with the compounds of the present invention. Suchinhibitors include but are not limited to inhibitors of JNK1/2/3, PI3K,AKT and MEK, and 14.3.3 signaling inhibitors. Examples of AKT inhibitorsare described in PCT Publication No. WO 2007/058850, published 24 May2007 which corresponds to PCT Application No. PCT/US2006/043513, filed 9Nov. 2006. One particular AKT inhibitor disclosed therein is4-(2-(4-amino-1,2,5-oxadiazol-3-yl)-1-ethyl-7-{[(3S)-3-piperidinylmethyl]oxy}-1H-imidazo[4,5-c]pyridin-4-yl)-2-methyl-3-butyn-2-ol.

Cell cycle signaling inhibitors, including inhibitors of cyclindependent kinases (CDKs) are also useful in combination with thecompounds of the invention in the compositions and methods describedabove. Examples of cyclin dependent kinases, including CDK2, CDK4, andCDK6 and inhibitors for the same are described in, for instance, RosaniaG. R., et al., Exp. Opin. Ther. Patents (2000) 10:215-230.

Receptor kinase angiogenesis inhibitors may also find use in the presentinvention. Inhibitors of angiogenesis related to VEGFR and TIE-2 arediscussed above in regard to signal transduction inhibitors (both arereceptor tyrosine kinases). Other inhibitors may be used in combinationwith the compounds of the invention. For example, anti-VEGF antibodies,which do not recognize VEGFR (the receptor tyrosine kinase), but bind tothe ligand; small molecule inhibitors of integrin (alpha_(v) beta₃) thatinhibit angiogenesis; endostatin and angiostatin (non-RTK) may alsoprove useful in combination with the compounds of the invention. Oneexample of a VEGFR antibody is bevacizumab (AVASTIN®).

Inhibitors of phosphatidyl inositol-3-OH kinase family members includingblockers of PI3-kinase, ATM, DNA-PK, and Ku may also be useful incombination with the present invention.

Also of potential use in combination with the compounds of the inventionare myoinositol signaling inhibitors such as phospholipase C blockersand myoinositol analogues.

siRNA, RNAi, locked nucleic acid polynucleotides, and antisensetherapies may also be used in combination with the compounds of theinvention. Examples of such antisense therapies include those directedtowards the targets described above such as ISIS 2503 and gene therapyapproaches such as those using thymidine kinase or cytosine deaminase.Agents used in immunotherapeutic regimens may also be useful incombination with the compounds of the invention. Immunotherapeuticregimens include ex-vivo and in-vivo approaches to increasingimmunogenicity of patient tumor cells such as transfection withcytokines (eg. IL-2, IL-4, GMCFS and MCFS), approaches to increaseT-cell activity, approaches with transfected immune cells and approacheswith anti-idiotypic antibodies. Another potentially usefulimmunotherapeutic regimen is monoclonal antibodies with wild-type Fcreceptors that may illicit an immune response in the host (e.g., IGF-1Rmonoclonal antibodies).

Agents used in proapoptotic regimens (e.g., Bcl-2 antisenseoligonucleotides) may also be used in combination with the compounds ofthe invention. Members of the Bcl-2 family of proteins block apoptosis.Upregulation of Bcl-2 has therefore been linked to chemoresistance.Studies have shown that the epidermal growth factor (EGF) stimulatesanti-apoptotic members of the Bcl-2 family (i.e., mcl-1). Therefore,strategies designed to downregulate the expression of Bcl-2 in tumorshave demonstrated clinical benefit and are now in Phase II/III trials,namely Genta's G3139 bcl-2 antisense oligonucleotide. Such proapoptoticstrategies using the antisense oligonucleotide strategy for Bcl-2 arediscussed in Water, J. S., et al., J. Clin. Oncol. (2000) 18:1812-1823;and Kitada, S., et al., Antisense Res. Dev. (1994) 4:71-79.

Compounds of the invention may be prepared using the processes describedbelow. In all of the schemes described below, it is understood thatprotecting groups may be employed where necessary in accordance withgeneral principles known to those of skill in the art, for example, seeGreen, T. W. and Wuts, P. G. M. (1991) Protecting Groups in OrganicSynthesis, John Wiley & Sons. The selection of a particular protectinggroup and processes for installation and removal of protecting groups iswithin the skill of those in the art. The selection of processes forinstallation and removal of protecting groups as well as the reactionconditions and order of their execution shall be consistent with thepreparation of compounds of the invention.

Compounds of the invention, may be conveniently prepared by the methodsoutlined in Scheme 1 below.

-   -   wherein:    -   R¹⁰ is halo (preferably chloro) or thiomethyl;    -   E is a suitable carboxylic ester or carboxylic ester equivalent,        particularly a methyl ester, ethyl ester, or Weinreb's amide;    -   R^(a) is H or CH₃;    -   alk is alkyl or alkenyl; and    -   all other variables are as defined above.    -   In this and subsequent reaction Schemes, NBS is        N-bromosuccinimide.

The process for preparing the compounds of the invention according toScheme 1 (all formulas and all variables having been defined above)comprises the steps of:

-   a) reacting a compound of formula (II) with a compound of    formula (VII) to prepare a compound of formula (X);-   b) condensing the compound of formula (X) with a substituted    pyrimidine of formula (III) to prepare a compound of formula (XI);-   c) reacting the compound of formula (XI) with a suitable brominating    agent, followed by reacting with one of:    -   i) a thiourea,    -   ii) a formamide,    -   iii) an amide,    -   iv) a thioamide, or    -   v) a urea;    -   to prepare a compound of formula (VIII);-   d) reacting the compound of formula (VIII) with one of:    -   i) molecular hydrogen    -   ii) an alkyl metal reagent or alkenyl metal reagent    -   iii) an alcohol, or    -   iv) a compound of formula (IX): N(R^(a))—R⁸, wherein R^(a) is H        or CH₃, to prepare a compound of formula (I);-   e) optionally converting the compound of formula (I) to a    pharmaceutically acceptable salt thereof; and-   f) optionally converting the compound of formula (I) or a    pharmaceutically acceptable salt thereof to a different compound of    formula (I) or a pharmaceutically acceptable salt thereof.

The order of the foregoing steps is not critical to the processes of thepresent invention and the process may be carried out using any suitableorder of steps.

Compounds of formula (I) wherein R⁴ is H may be prepared by reacting acompound of formula (VIII) with a source of molecular hydrogen in thepresence of a transition metal catalyst.

-   -   wherein all variables are as defined above.

Appropriate conditions for the reduction reaction will be apparent tothose skilled in the art and include palladium hydroxide on carbon,palladium on carbon, sulfided platinum on carbon, or Raney nickel usingammonium formate or other suitable source of molecular hydrogen oralternatively under a hydrogen atmosphere. The reaction may be carriedout in an inert solvent at either atmospheric or elevated pressure. Thereaction may be carried out at a temperature of about 25° C. to 80° C.,preferably 50-70° C. Suitable inert solvents include but are not limitedto ethanol, methanol, and ethyl acetate.

Compounds of formula (I) wherein R⁴ is alkyl, haloalkyl, alkenyl,—R⁵—OR⁶, R⁵—CO₂R⁶, —R⁵—SO₂R⁶, —R⁵-Het or —R⁵—NR⁶R⁷, may be prepared byreacting a compound of formula (VIII) with an alkyl or alkenyl metalreagent such as compounds having the formula Alk_(n)MX_(m) orX_(m)MR⁵—CO₂R⁶

-   -   wherein Alk is alkyl or alkenyl;    -   n is 1, 2, 3 or 4;    -   M is a transition metal such as Zn, B or Sn;    -   X is halo, particularly Cl or Br;    -   m is 0, 1 or 2; and    -   all other variables are as defined above.

whereinR^(4a) is alkyl, haloalkyl, alkenyl, —R⁵—OR⁶, or R⁵—CO₂R⁶; andall other variables are as defined above.

Specific examples of suitable alkyl or alkenyl metal reagents includebut not limited to dialkylzinc, alkylzinc halides, alkylboranes,alkenylboranes, alkenylborates and alkenylstannanes, either foundcommercially or which can be prepared by those of ordinary skill in theart by conventional means.

In particular, the reaction is performed in the presence of a palladiumsource, optionally a phosphine ligand and optionally a base in asuitable inert solvent. Examples of suitable palladium sources includebut are not limited to bis(tri-t-butylphosphine)palladium (0),tris(dibenzylideneacetone)dipalladium (0),dichlorobis(triphenylphosphine)-palladium (II) oracetato(2′-di-t-butylphosphino-1,1′-biphenyl-2-yl)palladium (II).Examples of suitable phosphine ligands include but are not limited to9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene and triphenylphosphine.Examples of suitable bases include but are not limited to potassiumacetate, cesium carbonate, sodium methoxide, and triethylamine. Examplesof suitable inert solvents include but are not limited to THF, toluene,N,N-dimethylformamide or 1,4-dioxane, or isopropanol in the case ofalkenylborates. The reaction may be carried out at a temperature ofabout 25° C. to 100° C.

A compound of formula (I²) wherein R⁴ is alkenyl, may be converted to acompound of formula (I) wherein R⁴ is —R⁵—SO₂R⁶, —R⁵-Het or —R⁵—NR⁶R⁷ byreaction with an appropriate nucleophile. For example a compound offormula (I) wherein R⁴ is —R⁵—SO₂R⁶, or —R⁵NR⁶R⁷ may be prepared byreacting a compound of formula (I²) wherein R⁴ is alkenyl with a thiolor amine, respectively. Reaction conditions for such transformations areknown to those skilled in the art.

Compounds of formula (I) wherein R⁴ is —OR⁶, are prepared by reacting acompound of formula (VIII) with a suitable alcohol.

wherein all variables are as defined above.

Specific examples of suitable alcohols include but not limited tomethanol, ethanol, n-propanol or n-butanol. The reaction may optionallybe carried out in the presence of a base such as, but not limited tocesium carbonate, sodium methoxide, and triethylamine. The reaction istypically carried out at a temperature of about 50-120° C., atatmospheric or elevated pressure and optionally in a microwave.

Compounds of formula (I) wherein R⁴ is N(H)R⁸ (i.e., compounds offormula (I⁴)) are prepared by reacting a compound of formula (VIII) witha compound of formula (IX).

wherein R^(a) is H or CH₃ and all other variables are as defined above.

Those skilled in the art will recognize that the conditions required forthe above reaction will differ depending upon the definition of R¹⁰.When R¹⁰ is halo (preferably chloro), the reaction is generallyperformed in a solvent or neat. Suitable solvents include but are notlimited to isopropanol, methanol, 1,4-dioxane, ethanol,dimethylacetamide, trifluoroethanol, and N,N-dimethylformamide. Thereaction is typically carried out at a temperature of from about 30 toabout 120° C., or optionally in a microwave apparatus. In the embodimentwhere R⁴ is NH₂, the reaction is carried out with a source of ammonia,for example, ammonia in methanol or preferably ammonium hydroxide. Thereaction is typically carried out without the addition of other solventsand at temperatures of about 60° C. to about 120° C., in a sealedreaction vessel or optionally in a microwave apparatus. As will beapparent to those skilled in the art of organic chemistry, it may alsobe desirable to install appropriate protecting groups prior to reactingthe compound of formula (VIII) with the compound of formula (IX). Forexample, in the embodiment, wherein R⁴ is a group containing a pendantprimary or secondary amine, the addition is preferably carried out whenthe pendant amine is protected as, for example, its correspondingt-butyl carbamate or trifluoracetamide. The choice, installation andremoval of appropriate protecting groups for reactions such as this isconventional in the art. Compounds of formula (IX) are commerciallyavailable or may be synthesized using techniques conventional in theart.

When R¹⁰ is thiomethyl, the thiomethyl may first be converted to a moresuitable leaving group, for example sulfoxide, sulfone, or chloride. Thethiomethyl can be converted into a sulfoxide or sulfone by oxidationwith an appropriate oxidizing agent, for example oxone, sodiumperiodate, or meta-chloroperbenzoic acid, in an appropriate solvent, forexample dichloromethane, methanol, or water. Those skilled in the artwill recognize that this will produce an analogue of the compound offormula (VIII) in which R¹⁰ is a sulfoxide or sulfone. The oxidizedproduct can then be reacted with the compound of formula (IX) to preparea compound of formula (I).

These reactions are generally performed in a suitable solvent, forexample 2-propanol, dimethylacetamide, or dioxane, optionally with theaddition of acid, for example hydrochloric acid, and at a temperature of25-110° C., preferably 70-90° C., or in a microwave reactor at atemperature of 90-220° C., preferably 160-190° C.

Alternately, the pyrimidinyl sulfoxide or sulfone can be converted tothe corresponding hydroxyl pyrimidine by reaction with an appropriateaqueous acid, for example hydrochloric acid or acetic acid, at atemperature of 25-110° C., preferably 70-90° C. The hydroxyl pyrimidinecan then be converted to a chloride using an appropriate chlorinatingreagent, for example phosphorous oxychloride or thionyl chloride,optionally in a solvent, for example dichloromethane, at a temperatureof 25-120° C., preferably 60-80° C. Those skilled in the art willrecognize that this process will produce a compound of formula (VIII)wherein R¹⁰ is chloro, which can be reacted with a compound of formula(IX) as described above.

Compounds of formula (VIII) may be prepared by reacting a compound offormula (XI) with a suitable brominating reagent, particularly bromineor NBS, followed by reacting with one of: 1) a thiourea, 2) a formamide3) an amide 4) a thioamide or 5) a urea depending upon whether thethiazole or oxazole and which particular substituents R³, are desired.

wherein all variables are as defined above.

In this and subsequent Schemes, reference to thiourea, formamide, amide,thioamide or urea in connection with this type of reaction refers tounsubstituted thiourea, formamide, amide, thioamide or urea andsubstituted analogs thereof. In particular, the thiourea, formamide,amide, thioamide or urea may be substituted with the desired group R³.Suitably substituted analogs of thiourea, formamide, amide, thioamide orurea are commercially available or may be prepared using conventionaltechniques.

When an aminothiazole (i.e., the compound of formula (VIII) wherein W isS and R³ is —NR⁶R⁷ or Het is desired, the reaction can be accomplishedby the initial bromination of a compound of formula (XI) using anappropriate brominating reagent, for example bromine in solvent such asacetic acid or NBS.

The reaction is typically carried out in an appropriate solvent, forexample dichloromethane, N,N-dimethylformamide, orN,N-dimethylacetamide, and at a temperature of 25-50° C., particularly25° C. The brominated analog (i.e., a compound of formula (XI-A)) isthen reacted with an appropriately substituted thiourea.

wherein W is S, R^(3a) is —NR⁶R⁷ or Het and all other variables are asdefined above.

The reaction is typically carried out in an appropriate solvent, forexample, N,N-dimethylformamide, N,N-dimethylacetamide, dichloromethane,tetrahydrofuran, dioxane, or acetonitrile, optionally in the presence ofa suitable base, for example magnesium carbonate or sodium bicarbonate,and at a temperature of 25-90° C., particularly 25-50° C. Those skilledin the art will recognize that the thiourea can be unsubstituted, thusresulting in a compound of formula (VIII) wherein R³ is NH₂; or thethiourea may bear one or more additional substituents on one of thenitrogen atoms.

In this and subsequent reactions, a compound, such as a compound offormula (VIII), wherein R³ is an amino group (i.e., —NR⁶R⁷), may befurther converted to a corresponding compound wherein R³ is other thanamino (or substituted amino) using the techniques described herein andthose conventional in the art.

For example, the aminothiazole compound of formula (VIII-A) wherein R³is an amino group, may be converted to an unsubstituted thiazole (i.e.,a compound of formula (VIII) wherein R³ is H) using methods familiar tothose of skill in the art. For example, the thiazole may be prepared byreacting the aminothiazole with an appropriate reagent, for examplet-butyl nitrite, in an appropriate solvent, for example tetrahydrofuran,and at a temperature of 35-75° C., particularly 40-60° C.

When a substituted thiazole is desired, an aminothiazole of formula(VIII) may be modified according to methods that will be familiar tothose skilled in the art. For example, the aminothiazole compound offormula (VIII-A) may be converted to a compound of formula (VIII-B) byreaction with reagents capable of replacing the amino group with ahalide, preferably a bromide.

-   -   wherein Hal is halo, preferably Br; and all other variables are        as defined above.

The conversion to a halo-thiazole of formula (VIII-B) may be carried outby reaction with for example, t-butyl nitrite and copper (II) bromide ina suitable solvent, such as tetrahydrofuran or acetonitrile, and at atemperature from −10° C. to 50° C., preferably 0° C. to 25° C. Thehalo-thiazole of formula (VIII-B), may then be reacted under a varietyof conditions known to those in the art to produce different thiazolecompounds of formula (VIII-C) wherein R³ can be a variety ofsubstituents consistent with the definition of R³ in reference tocompounds of Formula (I).

One example of such a reaction is similar to the method of J. Tsuji“Palladium Reagents and Catalysts: Innovations in Organic Synthesis”,Wiley, Chichester, UK, 1995, involving reaction of the halo-thiazole offormula (VIII-B) with a reagent capable of undergoing palladium-basedcoupling to prepare compounds of formula (VIII-C) wherein R^(3c) isalkyl, haloalkyl, or alkenyl.

-   -   wherein Hal is halogen;    -   R^(3c) is alkyl, haloalkyl or alkyl-OH; and    -   all other variables are as defined above.

For example the halo-thiazole of formula (VIII-B) may be reacted with aboronic acid, boronate ester, alkyl tin, alkyl zinc or Grignard reagent,in an appropriate solvent, for example tetrahydrofuran, dioxane, ordimethylformamide, in the presence of a catalyst capable of inducingsuch a transformation, particularly a palladium catalyst, for examplepalladiumdicholorobistriphenylphosphine, and at a temperature of 25-150°C., preferably 25-60° C. Those skilled in the art will recognize thatthese coupling reactions will often require the addition of a suitablebase, such as aqueous sodium carbonate, cesium carbonate, ortriethylamine and/or the addition of a suitable ligand for the palladiumspecies, for example a trialkylphosphine or a triarylphosphine, forexample triphenylphosphine.

Another example of such a reaction involves the reaction of thehalo-thiazole of formula (V-B) with a reagent capable of displacing thebromide, for example an amine, such as piperidine, methylamine, ormethyl piperazine.

-   -   wherein Hal is halogen;    -   R^(3d) is —NR⁶R⁷; and    -   all other variables are as defined above.

In the case of reacting a halo-thiazole of formula (VIII-B) with anamine or substituted amine (e.g., dimethylamine) the reaction isgenerally performed by reacting the compound of formula (V-B) with theamine or substituted amine optionally in a suitable solvent, such as2-propanol, dioxane, or dimethylformamide, at a temperature of 25° C. to150° C., preferably 50-90° C., optionally in the presence of a suitableacid, for example hydrochloric acid.

According to another process of producing a substituted thiazole offormula (VIII), a compound of formula (XI-A) is reacted with athioamide, for example thioacetamide, to prepare a compound of formula(VIII-D) wherein R^(3d) is alkyl.

-   -   wherein all variables are as defined above.

Alkyl substituted thioamides for use in this process are commerciallyavailable or may be prepared using conventional techniques. Typically,the reaction is carried out in an appropriate solvent, for example,dichloromethane, tetrahydrofuran, dimethylformamide,N,N-dimethylacetamide, or acetonitrile, particularly dimethylformamideor N,N-dimethylacetamide, optionally in the presence of a suitable base,for example magnesium carbonate or sodium bicarbonate, and at atemperature of 35-100° C., preferably 50-80° C.

In the embodiment wherein an oxazole of formula (VIII) is desiredwherein R³ is H, the reaction can be accomplished by reacting thecompound of formula (XI-A) with formamide in the presence of an acid,such as sulfuric acid, and at a temperature of 60-150° C., preferably90-130° C.

wherein all variables are as defined above.

A substituted oxazole of formula (VIII-F) may be prepared from thecompound of formula (XI-A).

wherein R^(3e) is Het or —NR⁶R⁷ and all other variables are as definedabove.

The reaction may be carried out by reacting the compound of formula(XI-A) with urea or substituted urea in an appropriate solvent, forexample, N,N-dimethylformamide, N,N-dimethylacetamide dichloromethane,tetrahydrofuran, dioxane, or acetonitrile, optionally in the presence ofa suitable base, for example magnesium carbonate or sodium bicarbonate,and at a temperature of 25-170° C., particularly 60-150° C. or in amicrowave reactor at a temperature of 100-190° C., particularly 120-160°C. Those skilled in the art will envision substituted ureas that may beemployed in the foregoing method to prepare compounds of formula(VIII-F) wherein R^(3e) is as defined above. One example of asubstituted urea for use in this method is 1-pyrrolidinecarboxamide.Suitable substituted ureas are commercially available or can be madeusing techniques known to those skilled in the art.

A substituted oxazole of formula (VIII-G), may also be prepared from acompound of formula (XI-A).

-   -   wherein R^(3f) is alkyl or haloalkyl and all other variables are        as defined above.

Typically, the reaction may be carried out by reacting the compound offormula (XI-A) with an amide (i.e., a compound of formulaR^(3f)—C(O)NH₂), for example acetamide, in an appropriate solvent, forexample, dichloromethane, tetrahydrofuran, dimethylformamide, oracetonitrile, particularly dimethylformamide or neat, optionally in thepresence of a suitable base, for example magnesium carbonate or sodiumbicarbonate, and at a temperature of 35-170° C., preferably 60-150° C.or in a microwave reactor at a temperature of 100-190° C., particularly130-170° C. Suitable amides for use in this reaction will be apparent tothose skilled in the art and are commercially available or may beprepared using conventional techniques.

As will be appreciated by those skilled in the art a bromo-substitutedoxazole of formula (VIII-H),

-   -   wherein all other variables are as defined above;        may also be prepared by conversion of an oxazole of formula        (VIII-F) (wherein R³ is an amine or substituted amino group) to        the bromo analog using techniques known to those of skill in the        art, including those described above.

Those of skill in the art will recognize that some of the reactionsdescribed above may be incompatible with compounds of formula (VIII) inwhich R¹⁰ is chloride. In such embodiments, the foregoing reactions maybe performed using compounds of formula (XI) wherein R¹⁰ is thiomethyl,and subsequently converting the thiomethyl to a more suitable leavinggroup, such as a sulfoxide, sulfone or chloride using techniquesconventional in the art, including those described above.

Compounds of formula (XI) may be prepared by reacting a compound offormula (X) with a substituted pyrimidine of formula (III).

-   -   wherein all variables are as defined above.

The reaction is generally performed by reacting a compound of formula(X) and a compound of formula (III) in the presence of a suitable basecapable of deprotonating a compound of formula (III), for examplelithium hexamethyldisilazide (LiHMDS), sodium hexamethyldisilazide, orlithium diisopropylamide, particularly LiHMDS, in an appropriatesolvent, such as THF, and at a temperature of about −78° C. to about 25°C., particularly about 0° C. to about 25° C.

A compound of formula (X) may be prepared by reacting the compound offormula (II) with a compound of formula (VII).

This reaction may be carried out using conditions conventional in theart for such coupling reactions, including the use of a solvent such astetrahydrofuran, 1,4-dioxane or dichloromethane at room temperature orwith heating from about 40° C. to about 100° C. Those skilled in the artwill recognize that it may be desirable to carry out this reaction inthe presence of a suitable base, for example pyridine or triethylamine.Compounds of formula (VII) are commercially available or may besynthesized using techniques conventional in the art.

Compounds of formula (II) wherein Q¹, Q², Q³ and Q⁴ are CH arecommercially available. Compounds of formula (II) wherein one of Q¹, Q²,Q³ and Q⁴ is C—R² may be prepared by reduction of the compound offormula (XIII). Appropriate conditions for the reduction reaction willbe apparent to those skilled in the art and include palladium on carbonunder a hydrogen atmosphere, sulfided platinum on carbon under ahydrogen atmosphere, or iron powder in acetic acid. In one embodiment,the reduction may be effected using Raney nickel under a hydrogenatmosphere. The reaction may be carried out in an inert solvent ateither atmospheric or elevated pressure. Suitable inert solvents includebut are not limited to ethanol, methanol, and ethyl acetate.

Compounds of formula (XIII) may be prepared by oxidation of the compoundof formula (XX) using an appropriate oxidizing agent such as but notlimited to chromium trioxide or potassium permanganate to yieldcompounds of formula (XXI). In one embodiment, the reaction is performedwith chromium trioxide under strongly acidic conditions such as in thepresence of sulfuric acid. The reaction may be carried out at atemperature of about 80° C. to 100° C. Compounds of formula (XXI) can bethen converted to compounds of formula (XIII) by esterification of theacid functionality using conditions standard for such transformations,specifically in methanol in the presence of catalytic sulfuric acid.

-   -   wherein all variables are as defined above.

Alternatively, compounds of formula (II) wherein one of Q¹, Q², Q³ andQ⁴ is C—R² may be prepared by reaction of the compound of formula (XV)with a nitrogen source such as benzophenone imine or t-butyl carbamateusing conditions conventional in the art for Buchwald cross-couplingreactions. In particular, in the presence of a palladium source,optionally a phosphine ligand, and a base in a suitable inert solvent.Examples of suitable palladium sources include but are not limited totris(dibenzylideneacetone)dipalladium (0),dichlorobis(triphenylphosphine)-palladium (II) oracetato(2′-di-t-butylphosphino-1,1-biphenyl-2-yl)palladium (II).Examples of suitable phosphine ligands include but are not limited to9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene and triphenylphosphine.Examples of suitable bases include but are not limited to potassiumacetate, cesium carbonate, sodium methoxide, and triethylamine. Examplesof suitable inert solvents include but are not limited to toluene,N,N-dimethylformamide or 1,4-dioxane. The reaction may be carried out ata temperature of about 80° C. to 150° C., optionally in the microwave.

-   -   wherein X is halo, particularly Br;    -   P is protected nitrogen, particularly benzophenone imine or        t-butyl carbamate;    -   and all other variables are as defined above.

Conversion of compounds of formula (XVI) to compounds of formula (II)can be achieved by reaction with a strong acid in a suitable organicsolvent using conventional acidic deprotection techniques. Suitableacids used in such transformations include but are not limited tohydrochloric acid. Suitable solvents for such transformations includebut are not limited to tetrahydrofuran and 1,4-dioxane. See, Kocienski,P. J. Protecting Groups, Georg Thieme Verlag, Stuttgart, 1994; andGreene, T. W., Wuts, P. G. M. Protecting Groups in Organic Synthesis(2^(nd) Edition), J. Wiley and Sons, 1991.

As noted above, the order of the foregoing steps is not critical to thepractice of the present invention. In another embodiment, compounds ofthe invention may also be prepared according to Scheme 2, whichdemonstrates an alternative order of the steps of Scheme 1.

wherein:

-   R¹⁰ is halo (preferably chloro) or thiomethyl;-   E is a suitable carboxylic ester or ester equivalent, particularly a    methyl ester, ethyl ester, or Weinreb's amide;-   Alloc is allylchloroformate;-   Bu₃SnH is tri-n-butyl tin hydride; and-   all other variables are as defined above.

The process according to Scheme 2 comprises the steps of:

-   a) installing a protecting group such as allylchloroformate, on a    compound of formula (II) to prepare a compound of formula (II-A);-   b) condensing the compound of formula (II-A) with a substituted    pyrimidine compound of formula (III) to prepare a compound of    formula (IV);-   c) reacting the compound of formula (IV) with a suitable brominating    agent followed by one of:    -   i) a thiourea,    -   ii) a formamide,    -   iii) an amide,    -   iv) a thioamide, or    -   v) a urea;    -   to prepare a compound of formula (V);-   d) reacting the compound of formula (V) in the presence of a    Palladium catalyst to prepare a compound of formula VI;-   e) reacting a compound of formula (VI) with a compound of    formula (VII) to prepare a compound of formula (VIII);-   f) reacting the compound of formula (VIII) with one of:    -   i) molecular hydrogen    -   ii) an alkyl metal reagent or alkenyl metal reagent    -   iii) an alcohol, or    -   iv) a compound of formula (IX),        -   to prepare a compound of formula (I);-   g) optionally converting the compound of formula (I) to a    pharmaceutically acceptable salt thereof; and-   h) optionally converting the compound of formula (I) or a    pharmaceutically acceptable salt thereof to a different compound of    formula (I) or a pharmaceutically acceptable salt thereof.

The installation and removal of the Alloc protecting group may beachieved using conventional means. For example, the compound of formula(II) may be reacted with allylchloroformate using conventional acylationconditions to those skilled in the art for the installation of carbamateprotecting groups. Removal of the protecting group may be achieved byreacting the compound of formula (V) with tributyltin hydride in thepresence of a Pd catalyst and weak acid. In one embodimentdichlorobis(triphenylphosphine)-palladium (II) was used along withacetic acid. A variety of solvents may be used including but not limitedto dichloromethane, toluene, diethyl ether, acetone andN,N-dimethylformamide. See, Kocienski, P. J. Protecting Groups, GeorgThieme Verlag, Stuttgart, 1994; and Greene, T. W., Wuts, P. G. M.Protecting Groups in Organic Synthesis (2^(nd) Edition), J. Wiley andSons, 1991.

The remaining steps of the reaction may be carried out generally in themanner described above for the analogous steps in Scheme 1.

As a further example of changing the order of the steps, compounds ofthe invention may also be prepared according to Scheme 3.

-   -   wherein R¹⁰ is halo (preferably chloro) or thiomethyl, and all        other variables are as defined above.

Generally, the process for preparing the compounds of the inventionaccording to Scheme 3 (all formulas and all variables having beendefined above) comprises the steps of:

-   a) reacting the compound of formula (V) with one of:    -   i) molecular hydrogen    -   ii) an alkyl or alkenyl metal reagent    -   iii) an alcohol, or    -   iv) a compound of formula (IX),    -   to prepare a compound of formula (XVIII);-   b) reacting the compound of formula (XVII) in the presence of a    Palladium catalyst to prepare a compound of formula (XVIII);-   c) reacting the compound of formula (XVIII) with a compound of    formula (VII) to prepare a compound of formula (I);-   d) optionally converting the compound of formula (I) to a    pharmaceutically acceptable salt thereof; and-   e) optionally converting the compound of formula (I) or a    pharmaceutically acceptable salt thereof to a different compound of    formula (I) or a pharmaceutically acceptable salt thereof.

Each of the foregoing steps may be carried out using the techniquesdescribed above for analogous reactions with different startingmaterials.

It will be appreciated by those skilled in the art that the optimalchoice of the reaction sequence employed to prepare a particularcompound of the invention may depend upon the specific compound of theinvention that is desired as well as the preference and availability ofstarting materials.

As will be apparent to those skilled in the art, a compound of formula(I) may be converted to another compound of formula (I) using techniqueswell known in the art. For example, compounds of formula (I) may bemodified using conventional techniques to modify or diversify the groupsdefined by the variable R³ and thereby provide different compounds offormula (I). Specifically, a compound of formula (I-1) (wherein R³ is—NH₂) may be converted to a compound of formula (I-2) by reductiveamination of the amine with acetone and sodium cyanoborohydride.

wherein all variables are as defined above.

A compound of formula (I-1) may also be converted to a compound offormula (I-3) by reacting with mesyl chloride.

wherein all variables are as defined above.

Based upon this disclosure and the examples contained herein one skilledin the art can readily convert a compound of formula (I) or apharmaceutically acceptable salt thereof into a different compound offormula (I), or a pharmaceutically acceptable salt thereof.

The present invention also provides radiolabeled compounds of formula(I) and biotinylated compounds of formula (I) and solid-support-boundversions thereof, i.e. a compound of formula (I) having a radiolabel orbiotin bound thereto. Radiolabeled compounds of formula (I) andbiotinylated compounds of formula (I) can be prepared using conventionaltechniques. For example, radiolabeled compounds of formula (I) can beprepared by reacting the compound of formula (I) with tritium gas in thepresence of an appropriate catalyst to produce radiolabeled compounds offormula (I). In one embodiment, the compounds of formula (I) aretritiated.

The radiolabeled compounds of formula (I) and biotinylated compounds offormula (I) are useful in assays for the identification of compoundswhich inhibit at least one Raf family kinase, for the identification ofcompounds for the treatment of a condition capable of being treated witha Raf inhibitor, e.g., for the treatment of neoplasms susceptible totreatment with a Raf inhibitor. The present invention also provides anassay method for identifying such compounds, which method comprises thestep of specifically binding a radiolabeled compound of the invention ora biotinylated compound of the invention to the target protein orcellular homogenate. More specifically, suitable assay methods willinclude competition binding assays. The radiolabeled compounds of theinvention and biotinylated compounds of the invention andsolid-support-bound versions thereof, can also be employed in assaysaccording to the methods conventional in the art.

The following examples are intended for illustration only and are notintended to limit the scope of the invention in any way. The inventionis defined by the claims which follow.

EXAMPLES

As used herein, the symbols and conventions used in these processes,schemes and examples are consistent with those used in the contemporaryscientific literature, for example, the Journal of the American ChemicalSociety or the Journal of Biological Chemistry. Standard single-letteror three-letter abbreviations are generally used to designate amino acidresidues, which are assumed to be in the L-configuration unlessotherwise noted. Unless otherwise noted, all starting materials wereobtained from commercial suppliers and used without furtherpurification. Specifically, the following abbreviations may be used inthe examples and throughout the specification:

atm (atmosphere); g (grams); mg (milligrams); h (hour(s)); min(minutes); Hz (Hertz); MHz (megahertz); i.v. (intravenous); L (liters);mL (milliliters); μL (microliters); M (molar); mM (millimolar); mol(moles); mmol (millimoles); mp (melting point); psi (pounds per squareinch); rt (room temperature); TLC (thin layer chromatography); T_(r)(retention time); RP (reverse phase; H₂ (hydrogen); N₂ (nitrogen) Ac(acetyl); ACN (acetonitrile); Ac₂O (acetic anhydride); ATP (adenosinetriphosphate); BOC (tert-butyloxycarbonyl); BSA (bovine serum albumin)CHCl₃ (chloroform); mCPBA (meta-chloroperbenzoic acid); DCC(dicyclohexylcarbodiimide); DCE (dichloroethane); DCM (CH₂Cl₂;dichloromethane); DIEA (N,N-Diisopropylethylamine); DMA (dimethylacetamide); DMAP (4-dimethylaminopyridine); DME (1,2-dimethoxyethane);DMEM (Dulbecco's modified Eagle medium); DMF (N,dimethylformamide); DMSO(dimethylsulfoxide); EDC (ethylcarbodiimide hydrochloride); EDTA(ethylenediaminetetraacetic acid); Et (ethyl; —CH₂CH₃) EtOH (ethanol);EtOAc (ethyl acetate); FBS (fetal bovine serum); FMOC(9-fluorenylmethoxycarbonyl); HATU (O-(7-Azabenzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate); HCl (hydrochloricacid) HEPES (4-(2-hydroxyethyl)-1-piperazine ethane sulfonic acid); Hex(hexanes); HOAc (acetic acid); HPLC (high pressure liquidchromatography); i-PrOH (isopropanol); K₂CO₃ (potassium carbonate); KOH(potassuim hydroxide); LiHMDS (lithium hexamethyldisilazide); LiOH(lithium hydroxide); LiOH•H₂O (lithium hydroxide monohydrate); Me(methyl; —CH₃) MeOH (methanol); MgCO₃ (magnesium carbonate); MgSO₄(magnesium sulfate); Na₂CO₃ (sodium carbonate); NaHCO₃ (sodiumbicarbonate); NaH (sodium hydride) Na₂SO₄ (sodium sulfate); NaHSO₄(sodium bisulfate); NBS is N-bromosuccinamide; NH₄OH (ammoniumhydroxide); Pd(PPh₃)₂Cl₂ (bis(triphenylphosphine)- palladium (II)chloride); PdCl₂(dppf) (dichloro[1,1′bis(diphenyl-phosphino)ferrocene]palladium (II) dichloromethane adduct; TBAF(tetrabutylammonium fluoride); TEA (triethylamine); TFA (trifluoroaceticacid); THF (tetrahydrofuran); TIPS (triisopropylsilyl); TMS(trimethylsilyl); and TMSE (2-(trimethylsilyl)ethyl); and TsOH(p-Toluenesulfonic acid).

All references to ether are to diethyl ether; brine refers to asaturated aqueous solution of NaCl. Unless otherwise indicated, alltemperatures are expressed in ° C. (degrees Centigrade). All reactionsare conducted under an inert atmosphere at rt unless otherwise noted.

¹H-NMR spectra were recorded on a Varian VXR-300, a Varian Unity-300, aVarian Unity-400 instrument, a General Electric QE-300, a Bruker 300, ora Bruker 400. Chemical shifts are expressed in parts per million (ppm, δunits). Coupling constants are in units of hertz (Hz). Splittingpatterns describe apparent multiplicities and are designated as s(singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br(broad).

Low-resolution mass spectra (MS) were recorded on a Agilent LCMS, JOELJMS-AX505HA, JOEL SX-102, a SCIEX-APIiii, a Finnegan MSQ, Waters SQD,Waters ZQ, or a Finnegan LCQ spectrometer; high resolution MS wereobtained using a JOEL SX-102A spectrometer. All mass spectra were takenunder electrospray ionization (ESI), chemical ionization (CI), electronimpact (EI) or by fast atom bombardment (FAB) methods. All reactionswere monitored by thin-layer chromatography on 0.25 mm E. Merck silicagel plates (60E-254), visualized with UV light, 5% ethanolicphosphomolybdic acid or p-anisaldehyde solution or mass spectrometry(electrospray or AP). Flash column chromatography was performed onsilica gel (230-400 mesh, Merck) or using automated silica gelchromatography (Isco, Inc. Sq 16x or 100sg Combiflash). Reported HPLCretention times (RT) were obtained on a Waters 2795 instrument attachedto a Waters 996 diode array detector reading 210-500 nm. The column usedwas a Synergi Max-RP (50×2 mm) model #00B-4337-B0. Solvent gradient was15% MeOH:water to 100% MeOH (0.1% formic acid) over 6 min. Flow rate was0.8 mL/min. Injection volume was 3 μL.

Intermediate 1 2-Methylpropanethioamide

A solution of 2-methylpropanamide (6.53 g, 75.0 mmol) and2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide(15.17 g, 37.51 mmol) in THF (100 mL) was heated to reflux for 4 h. Thereaction mixture was then cooled to rt and poured into saturated aqueousNaHCO₃ (200 mL). The mixture was extracted with ether (4×100 mL). Theorganic fractions were combined, dried over Na₂SO₄, filtered, andconcentrated. Purification by flash column chromatography (20%EtOAc:hexanes) afforded 4.77 g (62%) of the title compound. ¹H-NMR (400MHz, CDCl₃) δ 7.63 (brs, 1H), 6.90 (brs, 1H), 2.88 (m, 1H), and 1.27 (d,6H, J=6.8 Hz).

Intermediate 2 1-Pyrrolidinecarbothioamide

To obtain the title compound, pyrrolidine (1.5 g, 21 mmol) was placed ina round bottom flask under N₂ with stirring. THF (4 mL) was addedfollowed by the drop-wise addition of 4N HCl in dioxane (5.3 mL, 21mmol). Potassium thiocyanate (2.0 g, 21 mmol) was then added in oneportion to the stirring solution of pyrrolidine hydrochloride. Thismixture was then stirred at rt for 30 min followed by heating at 100° C.for 2 h. The reaction was then cooled to rt, MeOH (50 mL) was added, andsolids that persisted were filtered away. Subsequent concentration ofthe MeOH/reaction solution yielded 3.0 g of the crude1-pyrrolidinecarbothioamide. ¹H-NMR (400 MHz, DMSO-d₆) δ 8.60 (brs, 2H),3.07 (m, 4H), and 1.82 (m, 4H).

Intermediate 3 2,2-Dimethylpropanethioamide

The title compound was prepared (3.2 g, 36%) from2,2-dimethylpropanamide (7.59 g, 75.0 mmol) and2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide(15.17 g, 37.51 mmol) by a procedure analogous to Intermediate 1. ¹H-NMR(400 MHz, CDCl₃) δ 7.92 (brs, 1H), 7.03 (brs, 1H), and 1.38 (s, 9H).

Intermediate 4 Tetrahydro-2H-pyran-4-carbothioamide

A solution of tetrahydro-2H-pyran-4-carboxamide (9.47 g, 73.3 mmol) andLawesson's reagent (14.83 g, 36.7 mmol) in THF (98 mL) was heated toreflux for 6 h. The reaction was cooled to rt, poured into saturatedaqueous NaHCO₃ (200 mL) and extracted with diethyl ether (4×100 mL). Thecombined organic extracts were dried over Na₂SO₄, filtered, andconcentrated. The residual solid was triturated with 1:1 EtOAc:hexanes(100 mL) and filtered to collect the solid. The filtrate wasconcentrated and re-subjected to trituration and filtration using thesame conditions. The combined solids were dried under vacuum to affordtetrahydro-2H-pyran-4-carbothioamide (4.91 g, 32.1 mmol, 43.8% yield) asa white solid. ¹H NMR (400 MHz, CDCl₃) δ ppm 7.49 (br. s., 1H), 6.84(br. s., 1H), 3.94-4.32 (m, 2H), 3.31-3.62 (m, 2H), 2.52-3.03 (m, 1H),1.81-1.93 (m, 4H).

Intermediate 5N-{3-[(Z)-2-(2-Chloro-4-pyrimidinyl)-1-hydroxyethenyl]phenyl}-2,6-difluorobenzenesulfonamide

Step A: Ethyl 3-{[(2,6-difluorophenyl)sulfonyl]amino}benzoate

To a solution of ethyl-3-aminobenzoate (50 mL, 333 mmol) and2,6-difluorobenzenesulfonyl chloride (44.2 mL, 333 mmol) in DCM (300 mL)at 0° C. was added pyridine (32.2 mL, 400 mmol). The reaction mixturewas warmed to rt, stirred for 36 h, and quenched with 2 mL NH₃ (7M inMeOH). The suspension washed with 10% NaHSO₄ and the organic extractscombined and passed through a short column of silica gel. Residualmaterial was flushed from the column with 10% MeOH/EtOAc. The organicextracts were combined and the solvent removed under reduced pressure toprovide 107.9 g (95%) of the title compound of Step A. ¹H-NMR (400 MHz,DMSO-d6) δ ppm 11.20 (s, 1H), 7.77 (s, 1H), 7.71 (t, J=7.4 Hz, 1H), 7.63(d, J=7.3 Hz, 1H), 7.35-7.49 (m, 2H), 7.29 (t, J=9.3 Hz, 2H), 4.28 (q,J=7.1 Hz, 2H), and 1.29 (t, J=7.1 Hz, 3H).

Step B:N-{3-[(Z)-2-(2-Chloro-4-pyrimidinyl)-1-hydroxyethenyl]phenyl}-2,6-difluorobenzenesulfonamide

To a stirring solution of ethyl3-{[(2,6-difluorophenyl)sulfonyl]amino}benzoate (47.9 g, 140 mmol) in100 mL anhydrous THF at 0° C. was added 1M LiHMDS in THF (421 mL, 421mmol). A solution of 2-chloro-4-methylpyrimidine (19.9 g, 154 mmol) in100 mL of anhydrous THF was added to the reaction mixture over 30 minand warmed to rt. The reaction mixture was quenched with 50 mL of MeOHand concentrated to a black solid under vacuum. The residue waspartitioned between DCM and 10% NaHSO₄. The aqueous and suspended solidswere extracted 2× with DCM and the combined organic extracts werefiltered through a pad of Celite, concentrated, and passed through ashort silica gel column (elution with THF) to provide 57 g (96%) of thetitle compound of Step B. ¹H-NMR (400 MHz, DMSO-d6) δ ppm 11.03-11.34(m, 1H), 8.49-8.91 (m, 1H), 7.79 (d, J=7.4 Hz, 1H), 7.65-7.76 (m, 2H),7.55-7.63 (m, 1H), 7.50 (t, J=7.7 Hz, 1H), 7.35-7.47 (m, 1H), 7.22-7.34(m, 2H), 6.43 (s, 1H), and 4.60 (s, 1H); ES-LCMS m/z 423.93 (M+H).

Intermediate 6N-{3-[5-(2-Chloro-4-pyrimidinyl)-2-(1-pyrrolidinyl)-1,3-thiazol-4-yl]phenyl}-2,6-difluorobenzenesulfonamide

To a stirring suspension ofN-{3-[(Z)-2-(2-chloro-4-pyrimidinyl)-1-hydroxyethenyl]phenyl}-2,6-difluorobenzenesulfonamide(1.0 g, 2.36 mmol, 1.0 eq) in DCM (˜5 mL) was added NBS (0.44 g, 2.48mmol, 1.05 eq). Upon formation of a red solution (˜10 minutes) thereaction mixture was concentrated to a solid and taken up in dioxane (10mL). To this solution was added MgCO₃ (0.38 g) followed by1-pyrrolidinecarbothioamide (0.384 g, 2.95 mmol, 1.25 eq). Afterstirring 3 h, the mixture was quenched with water (50 mL) and 1N HCl (10mL) and stirred 0.25 h. The mixture was filtered and the resultant solidtriturated with EtOAc/Hexanes to give 0.52 g (41%) of the titlecompound. ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 11.11 (s, 1H), 8.14 (d, J=5.7Hz, 1H), 7.65-7.74 (m, 1H), 7.41 (t, J=7.7 Hz, 1H), 7.18-7.29 (m, 5H),6.44 (d, J=5.5 Hz, 1H), 3.45-3.52 (m, 4H), and 1.98-2.05 (m, 4H).

Intermediate 7N-{3-[5-(2-Chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]phenyl}-2,6-difluorobenzenesulfonamide

Following a procedure analogous to the procedure described inIntermediate 6, usingN-{3-[(Z)-2-(2-chloro-4-pyrimidinyl)-1-hydroxyethenyl]phenyl}-2,6-difluorobenzenesulfonamide(1.00 g, 2.36 mmol) and 2,2-dimethylpropanethioamide (0.277 g, 2.36mmol) the title compound was obtained (690 mg, 53.3% yield). MS (ESI):521.1 [M+H]+.

Intermediate 8N-{3-[(Z)-2-(2-Chloro-4-pyrimidinyl)-1-hydroxyethenyl]phenyl}-2,5-difluorobenzenesulfonamide

Step A: Methyl 3-{[(2,5-difluorophenyl)sulfonyl]amino}benzoate

Following a procedure analogous to the procedure described inIntermediate 5, Step A using methyl 3-aminobenzoate (16 g, 105.9 mmol)in DCM (150 mL) and 2,5-difluorobenzene-1-sulfonyl chloride (24.7 g,116.5 mmol) the title compound was obtained (25.6 g, 73.8% yield). ¹HNMR (400 MHz, DMSO-d6) δ ppm 11.06-11.13 (br, 1H), 7.42-7.52 (m, 2H),7.52-7.77 (m, 4H), 7.78-7.80 (m, 1H), 3.88 (s, 3H).

Step B:N-{3-[(Z)-2-(2-Chloro-4-pyrimidinyl)-1-hydroxyethenyl]phenyl}-2,5-difluorobenzenesulfonamide

Following a procedure analogous to the procedure described inIntermediate 5, Step B using methyl3-(2,5-difluorophenylsulfonamido)benzoate (20.5 g, 62.7 mmol) and2-chloro-4-methylpyrimidine (8.8 g, 68.9 mmol) the title compound wasobtained (22.6 g, 85.3% yield). ¹H NMR (400 MHz, CDCl₃) δ ppm13.40-13.50 (br s), 10.95-11.12 (br s), 8.72-8.80 (m), 8.57-8.63 (m),7.77-7.82 (m), 7.36-7.72 (m), 7.22-7.30 (m), 6.43 (s), 4.52 (s); m/z(ES+): 424 [M+H]⁺.

Intermediate 9N-{3-[5-(2-Chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]phenyl}-2,5-difluorobenzenesulfonamide

To a solution ofN-{3-[(Z)-2-(2-chloro-4-pyrimidinyl)-1-hydroxyethenyl]phenyl}-2,5-difluorobenzenesulfonamide(1.0 g, 2.4 mmol) in 25 mL DMA, NBS (0.420 g, 2.4 mmol) was added andthe solution was allowed to stir 15 minutes at rt.2,2-Dimethylpropanethioamide (0.277 g, 2.359 mmol) was then added andthe reaction mixture was heated at 80° C. for 2 h. The reaction mixturewas diluted with EtOAc and washed with water×3. The organic layer wasdried over MgSO₄ and filtered. The organic solution was evaporated ontosilica gel and chromatographed. 0-50% EtOAc in DCM to give the titlecompound (1.01 g, 81% yield). ES-LCMS m/z 521.1 (M+H).

Intermediate 10N-{3-[5-(2-Chloro-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]phenyl}-2,5-difluorobenzenesulfonamide

The title compound was prepared fromN-{3-[(Z)-2-(2-chloro-4-pyrimidinyl)-1-hydroxyethenyl]phenyl}-2,5-difluorobenzenesulfonamide(1.5 g, 3.54 mmol), NBS (0.630 g, 3.54 mmol) and4-morpholinecarbothioamide (0.517 g, 3.54 mmol) by a procedure analogousto Intermediate 9. The title compound was obtained as a yellow solid(1.8 g, 90% yield). ES-LCMS m/z 549.7 (M+H).

Intermediate 11 2-Propen-1-yl{3-[(2-chloro-4-pyrimidinyl)acetyl]phenyl}carbamate

Step A: Ethyl 3-{[(2-propen-1-yloxy)carbonyl]amino}benzoate

A solution of ethyl-3-aminobenzoate (25.0 g, 151.33 mmol) in DCM (500mL) was cooled to 0° C. 2,6-Lutidine (19.46 g, 181.60 mmol) was added tothe solution followed by addition of 2-propen-1-yl chloridocarbonate(20.07 g, 166.46 mmol). Following addition, the reaction was removedfrom ice bath and stirred at rt for 30 min. The reaction was quenchedwith saturated NaHCO₃ and the layers were separated. The mixture wasextracted with DCM×3, and the combined organics were washed with 10%HCl/H₂O×3, dried over MgSO₄ and the solvent was removed to give thetitle compound of Step A (38.80 g, 80% yield). ¹H-NMR (400 MHz, DMSO-d₆)δ 9.96 (s, 1H), 8.15 (s, 1H), 7.66-7.72 (m, 1H), 7.59 (d, J=7.7 Hz, 1H),7.43 (t, J=7.9 Hz, 1H), 5.94-6.04 (m, 1H), 5.37 (dd, J=17.4 and 1.7 Hz,1H), 5.24 (dd, J=10.6 and 1.5 Hz, 1H), 4.63 (d, J=5.5 Hz, 2H), 4.31 (q,J=7.3 Hz, 2H), and 1.31 (t, J=7.1 Hz, 3H); ES-LCMS m/z 250 (M+H).

Step B: 2-Propen-1-yl{3-[(2-chloro-4-pyrimidinyl)acetyl]phenyl}carbamate

Ethyl 3-{[(2-propen-1-yloxy)carbonyl]amino}benzoate (20.0 g, 80.24 mmol)was dissolved in 1M LiHMDS in THF (260 mL) and cooled to 0° C. Asolution containing 2-chloro-4-methylpyrimidine (10.32 g, 80.24 mmol) in20 mL dry THF was added to the reaction mixture. The reaction wasstirred at 0° C. for 2 h, quenched with MeOH (100 mL), dried directlyonto silica, and purified via flash chromatography EtOAc/CH₂Cl₂ 0-100%gradient run over 60 min. The desired fractions were combined and thesolvent was removed to give the title compound (13.6 g, 51% yield);ES-LCMS m/z 332 (M+H).

Intermediate 12 2-Propen-1-yl{3-[5-(2-chloro-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]phenyl}carbamate

Following a procedure analogous to the procedure described inIntermediate 6, using 2-propen-1-yl{3-[(2-chloro-4-pyrimidinyl)acetyl]phenyl}carbamate (10.0 g, 30.14mmol), and 2-methylpropanethioamide (3.73 g, 36.17 mmol), prepared by aprocedure analogous to Intermediate 1, 5.74 g of the title compound wasobtained. MS (ESI): 415 [M+H]⁺.

Intermediate 133-[5-(2-chloro-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]aniline

To a solution containing 2-propen-1-yl{3-[5-(2-chloro-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]phenyl}carbamate(5.3 g, 12.77 mmol) and DCM (225 mL) was added tri-n-butyltin hydride(5.95 g, 20.43 mmol), followed bytrans-dichlorobis(triphenylphosphine)palladium (II) (0.53 g, 0.64 mmol)and HOAc (1.84 g, 30.65 mmol). At the conclusion of the reaction, silicawas added and the volatiles removed under reduced pressure. The residuewas purified by flash column chromatography with (84% DCM, 15% MeOH, and1% NH₄OH): DCM 0% to 100% to afford 3.4 g of the title compound. ¹H-NMR(400 MHz, DMSO-d₆) δ 8.57 (d, J=5.1 Hz, 1H), 7.16 (d, J=5.1 Hz, 1H),7.10 (t, J=7.7 Hz, 1H), 6.72-6.75 (m, 1H), 6.64-6.69 (m, 1H), 6.60-6.63(m, 1H), 5.28 (s, 2H), 3.27-3.40 (m, 1H), and 1.38 (d, J=7.0 Hz, 6H). MS(ESI): 331 [M+H]⁺.

Intermediate 14N-{3-[5-(2-Chloro-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]phenyl}-2,6-difluorobenzenesulfonamide

To a solution of3-[5-(2-chloro-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]phenylamine (1.0 g, 3.0 mmol), and pyridine (360 μL, 4.5 mmol) in DCM (50 mL)was added a solution of 2,6-difluorobenzenesulfonyl chloride (620 μL,4.5 mmol) in DCM (25 mL).

The reaction was stirred for 48 h at rt. The reaction mixture wasconcentrated, adsorbed onto silica gel, and purified via flashchromatography with 0-50% EtOAc/DCM to give 1.39 g (91% yield) of thetitle compound as a white powder. ES-LCMS m/z 507 (M+H).

Intermediate 15N-{3-[(2-Chloro-4-pyrimidinyl)acetyl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide

Step A: Methyl 3-bromo-2-fluorobenzoate

To a 100 mL round bottom flask was added 3-bromo-2-fluorobenzoic acid(10.4 g, 47.5 mmol), MeOH (100 mL, 2472 mmol) and sulfuric acid (6 mL,113 mmol). The reaction mixture was refluxed for 1 hr. After cooling tort, the MeOH was removed under reduced pressure and the acidic residuewas poured into cold water and EtOAc, the layers were separated and theaqueous layer was extracted with EtOAc. The organic layers werecombined, washed with brine, dried over NaSO₄ and concentrated underreduced pressure to afford 10.02 g of methyl 3-bromo-2-fluorobenzoate.¹H-NMR (400 MHz, DMSO-d₆) δ 7.95 (ddd, J=8.1, 6.4, and 1.7 Hz, 1H),7.82-7.87 (m, 1H), 7.26 (t, J=7.9 Hz, 1H), and 3.86 (s, 3H).

Step B: Methyl 3-amino-2-fluorobenzoate

In a 500 mL flask was placed 1,1-dimethylethyl carbamate (6.03 g, 51.5mmol), methyl 3-bromo-2-fluorobenzoate (10 g, 42.9 mmol),Pd₂(dba)₃.CHCl₃ (0.89 g, 0.86 mmol), xantphos (1.49 g, 2.57 mmol) andcesium carbonate (16.8 g, 51.5 mmol). The flask was sealed with a rubberseptum, placed under high vacuum, and toluene (200 mL) was added. Threecycles of high vacuum/N₂ were performed and the reaction mixture wasstirred at 90° C. overnight. The reaction was filtered through a pad ofcelite with EtOAc washing and concentrated. To the residue was added DCM(200 mL) followed by TFA (50 mL, 649 mmol), and the mixture was stirredat rt for 1 h. The volatiles were removed under reduced pressure and theresidue was taken up in EtOAc and washed with saturated NaHCO₃ andbrine. The organic layer was dried over NaSO₄, stripped onto silica andcolumn chromatographed on silica with 5% to 50% EtOAc:Hexane to give5.53 g (76%) of the title compound of Step B. ¹H-NMR (400 MHz, DMSO-d₆)δ 6.92-7.01 (m, 3H), 5.37 (s, 2H), and 3.81 (s, 3H). MS (ESI): 170[M+H]⁺.

Step C: Methyl 3-{[(2,6-difluorophenyl)sulfonyl]amino}-2-fluorobenzoate

In a 500 mL flask was placed methyl 3-amino-2-fluorobenzoate (5.5 g,32.5 mmol) and DCM (100 mL), and pyridine (2.9 mL, 35.8 mmol) was added.2,6-Difluorobenzenesulfonyl chloride (7.6 g, 35.8 mmol) in DCM (50 mL)was added dropwise via addition funnel and the reaction mixture wasallowed to stir at rt overnight. The reaction mixture was stripped ontosilica and column chromatographed on silica with 5% to 100% EtOAc:Hexaneto give 9.75 g (87%) of the title compound of Step C. ¹H-NMR (400 MHz,DMSO-d₆) δ 10.98 (s, 1H), 7.64-7.82 (m, 3H), 7.46-7.61 (m, 1H), 7.29 (t,J=8.8 Hz, 2H), and 3.81 (s, 3H). MS (ESI): 346 [M+H]⁺.

Step D:N-{3-[(2-Chloro-4-pyrimidinyl)acetyl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide

In a 1000 mL flask was placed methyl3-{[(2,6-difluorophenyl)sulfonyl]amino}-2-fluorobenzoate (9.64 g, 27.9mmol) and THF (200 mL) was added. The flask was placed in an ice/waterbath and LiHMDS (90 mL, 90 mmol) was added. 2-Chloro-4-methylpyrimidine(4.5 g, 35.0 mmol) in THF (60 mL) was added dropwise via additionfunnel. After the addition was complete, the reaction was allowed towarm to 20° C. over 1 h. The THF volume was reduced to half underreduced pressure and then treated with 6N HCl. EtOAc was added and thelayers were separated. The aqueous layer was extracted twice with EtOAcand the combined organic layer was washed once with brine, dried overNaSO₄, and concentrated. The residue was triturated with EtOAc/ether toafford 8.71 g (71%) of the title compound of Step D. MS (ESI): 442[M+H]⁺.

Alternative Method of Preparing methyl 3-amino-2-fluorobenzoate (Step Bof Intermediate 15, Above)

Step A: 2-fluoro-3-nitrobenzoic acid

Concentrated sulfuric acid (195 ml) was added carefully with stirring toa solution of 2-fluoro-3-nitrotoluene (100 g, 645 mmol) in acetic acid(1000 ml). The mixture was warmed up to 95° C. and the solution ofchromium trioxide (226 g, 2.25 mol) in water (200 ml) was added dropwisewith stirring over 2 h. After addition the mixture was heated withstirring for another 3 h, allowed to cool down to room temperature andpoured into water (3 L). The mixture was extracted with ethyl acetate(3×1 L), the combined organic layers were dried over Na₂SO₄ andconcentrated under reduced pressure to afford a light green solid, whichwas washed with dichloromethane (3×300 ml) and dried under vacuum toafford the title compound was obtained as a light yellow solid (75 g,62.8%). ¹H NMR (300 MHz, DMSO) δ ppm 8.27 (m, 1H), 8.15 (m, 1H), 7.48(m, 1H).

Step B: methyl 2-fluoro-3-nitrobenzoate

2-Fluoro-3-nitrobenzoic acid (75 g) was dissolved in 300 ml of methanol,and then 20 ml of concentrated H₂SO₄ was added. The mixture was stirredat 70° C. overnight and cooled to rt, the resulting solid was filteredand washed with water (3×200 ml), to the filtered was added water (400ml), the resulting precipitate was filtered and washed with water (2×100ml) to afford another batch of product. The solid were combined anddried under vacuum to afford the title compound was obtained as a lightyellow solid (78 g, 96%).

Step C: methyl 3-amino-2-fluorobenzoate

To a solution of methyl 2-fluoro-3-nitrobenzoate (78 g) in THF (400 ml)and methanol (100 ml) was added Raney Ni (40 g), the mixture was heatedto 70° C., and then 25 ml of hydrazine hydrate (N₂H₄.H₂O, 85%) was addeddropwise. The reaction was monitored by TLC, when the starting materialwas totally consumed the addition of hydrazine was stop. The mixture wascooled to rt and filtered, the filtrate was concentrated under vacuum toleave a brown oil, which was purified by chromatography (SiO₂, 300-400mesh, PE: EtOAc=11:2) to afford the title compound was obtained as ayellow oil (45 g, 68%). ¹H NMR (300 MHz, DMSO) δ ppm 6.96 (m, 3H), 5.36(s, 2H), 3.81 (s, 3H).

Intermediate 16N-{3-[5-(2-Chloro-4-pyrimidinyl)-2-(tetrahydro-2H-pyran-4-yl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide

To a solution ofN-{3-[(2-chloro-4-pyrimidinyl)acetyl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide(5.00 g, 11.3 mmol) in DMA (47.2 mL) was added NBS (2.115 g, 11.88mmol). The reaction stirred 30 min at rt and thentetrahydro-2H-pyran-4-carbothioamide (2.137 g, 14.71 mmol) was added.The reaction stirred 16 h at rt. The reaction mixture was poured intowater (500 mL), causing precipitation of a solid. The solid wascollected by vacuum filtration, re-dissolved in EtOAc (200 mL), andconcentrated onto silica gel. Purification by ISCO chromatography (20 to100% EtOAc:hexanes) afforded the title compound (3.58 g, 5.87 mmol,51.9% yield) as a light orange solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm10.93 (s, 1H), 8.55 (d, J=5.3 Hz, 1H), 7.58-7.79 (m, 1H), 7.38-7.52 (m,2H), 7.33 (t, J=7.9 Hz, 1H), 7.24 (t, J=9.1 Hz, 2H), 6.87 (d, J=5.1 Hz,1H), 3.84-4.00 (m, 2H), 3.41-3.54 (m, 2H), 3.31-3.39 (m, 1H), 1.92-2.13(m, 2H), 1.66-1.91 (m, 2H); m/z (ESI): 567.03 [M+H]⁺.

Intermediate 17N-{3-[5-(2-Chloro-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide

In a 250 mL flask was placedN-{3-[(2-chloro-4-pyrimidinyl)acetyl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide(4 g, 9.05 mmol) and DMF (60 mL) was added. NBS (1.62 g, 9.10 mmol) wasadded and, after stirring at rt for 40 min, 2-methylpropanethioamide(1.4 g, 13.6 mmol), prepared by a procedure analogous to Intermediate 1,was added. After 4 h at rt, the reaction mixture was poured into 800 mLof EtOAc and washed 4 times with 250 mL of H₂O, washed once with 200 mLof brine, and dried over NaSO₄. Silica gel was added and the volatileswere removed under reduced pressure. Column chromatography with 10% to60% EtOAc:Hexane gave 2.15 g (45%) of the title compound. ¹H-NMR (400MHz, DMSO-d₆) δ 11.43 (s, 1H), 9.06 (d, J=5.3 Hz, 1H), 8.12-8.30 (m,1H), 7.93-8.06 (m, 2H), 7.84 (t, J=7.9 Hz, 1H), 7.75 (t, J=9.2 Hz, 2H),7.37 (d, J=5.3 Hz, 1H), 3.77-3.93 (m, 1H), and 1.89 (d, J=6.8 Hz, 6H).MS (ESI): 524 [M]⁺.

Intermediate 18N-{3-[5-(2-Chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide

To a solution ofN-{3-[(2-chloro-4-pyrimidinyl)acetyl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide(2.0 g, 4.53 mmol) in 40 mL DMA, 1.0 eq. NBS (0.806 g, 4.53 mmol) wasadded and the solution was allowed to stir 15 min at rt.2,2-dimethylpropanethioamide (0.531 g, 4.53 mmol) was then added at rt.The reaction was heated to 60° C. for 2 hours. The reaction was notcomplete by LC-MS. The reaction mixture was then heated to 80° C. for anadditional hour. The reaction mixture was diluted with water andextracted×2 with EtOAc. The combined EtOAc washings were washed withwater×3 to remove DMA, dried over MgSO₄, filtered and concentrated ontosilica gel. The crude material was chromatographed in 10-80% EtOAc inHexanes to give the desired product, 1.6 g (64%). MS (ESI): 539.1[M+H]⁺.

Intermediate 19N-(3-(2-(2-Chloropyrimidin-4-yl)acetyl)-2-fluorophenyl)-2,5-difluorobenzenesulfonamide

Step A: Methyl 3-(2,5-difluorophenylsulfonamido)-2-fluorobenzoate

To a solution of methyl 3-amino-2-fluorobenzoate (21.8 g, 129 mmol) inDCM (300 mL) were added pyridine (30.6 g, 387.6 mmol) and a catalyticamount of DMAP. The mixture was cooled to 0° C.2,5-Difluorobenzene-1-sulfonyl chloride (28.8 g, 136 mmol) in DCM (20mL) was added dropwise to the mixture. The reaction was stirred at rtovernight. The reaction mixture was washed with water (300 mL), andextracted with DCM (2×200 mL). The organic layer was washed with brine,dried over anhydrous NaSO₄, filtered and concentrated under reducedpressure to give the crude product, which was washed with petroleumether to afford the title compound of Step A. (16 g, 35.9%). ¹H NMR (400MHz, DMSO-d6) δ ppm 10.71-10.91 (br, 1H), 7.65-7.73 (m, 1H), 7.48-7.62(m, 4H), 7.20-7.28 (m, 1H), 3.77 (s, 3H).

Step B:N-(3-(2-(2-Chloropyrimidin-4-yl)acetyl)-2-fluorophenyl)-2,5-difluorobenzenesulfonamide

To a solution of methyl3-(2,5-difluorophenylsulfonamido)-2-fluorobenzoate (44 g, 128 mmol (froma compilation of batches prepared as described above) in dry THF (500mL) at −10° C., LiHMDS (1M in THF, 448 mmol, 448 mL) was added dropwiseand the solution was allowed to stir for 1 h at 0° C. A solution of2-chloro-4-methylpyrimidine (19.4 g, 154 mmol) in THF (50 mL) was thenadded dropwise to the solution of ester and base at 0° C. over 20 min.The solution was allowed to stir 1 h at rt. TLC showed the reaction wascomplete. The reaction was quenched by addition of the saturated aqueousNH₄Cl (300 mL) at 0° C. The reaction mixture was extracted with EtOAc(500 mL×3). The combined organic layers were washed with water and brinesuccessively, dried over Na₂SO₄, filtered and concentrated under reducedpressure to give the crude product, which was purified by flash columnon silica gel, eluting with DCM. This solution was evaporated to obtaina solid. The orange solid was triturated with a small amount of EtOAcand filtered, rinsing with diethyl ether to give the title compound(18.6 g, 33.2% yield). ¹H NMR (400 MHz, CDCl₃) δ ppm 13.70-13.74 (br,1H), 8.59 (d, J=5.29 Hz, 0.3H), 8.42 (d, J=5.51 Hz, 1H), 7.75-7.79 (m,0.3H), 7.51-7.66 (m, 3.6H), 7.12-7.28 (m, 6.6H), 6.91 (d, J=5.51 Hz,1H), 6.03 (s, 1H), 4.37 (s, 0.6H). MS (ES+): 442 [M+H]⁺

Intermediate 20 2-Propen-1-yl{3-[(2-chloro-4-pyrimidinyl)acetyl]-2-fluorophenyl}carbamate

Step A: Methyl 3-(allyloxycarbonylamino)-2-fluorobenzoate

To a solution of methyl 3-amino-2-fluorobenzoate (200.0 g, 1183 mmol, 1eq) in THF (500 mL), saturated NaHCO₃ (1600 mL) was added. Then2-propen-1-yl chloridocarbonate (170.0 g, 1420 mmol, 1.2 eq) was addeddropwise at 0° C. The mixture was stirred at rt for 2 h. The solutionwas extracted with EtOAc (1 L×3). The combined organic layers werewashed with water and brine successively, dried over Na₂SO₄, filteredand concentrated under reduced pressure to give the crude product (260g, 86.9% yield), which was used in the next step directly. ¹H NMR (400MHz, DMSO-d₆) δ ppm 9.66 (s, 1H), 7.96 (t, J=7.6 Hz, 1H), 7.64 (t, J=6.4Hz, 1H), 7.33 (t, J=8.0 Hz, 1H), 6.07-6.00 (m, 1H), 5.43 (dd, J=1.6,17.6 Hz, 1H), 5.30 (dd, J=1.2, 10.4 Hz, 1H) 4.67 (d, J=5.6 Hz, 2H), 3.91(s, 3H).

Step B: 2-Propen-1-yl{3-[(2-chloro-4-pyrimidinyl)acetyl]-2-fluorophenyl}carbamate

To a solution of methyl 3-(allyloxycarbonylamino)-2-fluorobenzoate (86.7g, 342 mmol, 1 eq) in dry THF (500 mL) at −10° C., LiHMDS (1M in THF,1198 mmol, 1198 mL, 3.5 eq) was added dropwise and the solution wasallowed to stir for 1 h at 0° C. A solution of pyrimidine chloride (48.0g, 376 mmol, 1.2 eq) in THF (200 mL) was then added dropwise to thesolution of ester and base at 0° C. over 20 min. The solution wasallowed to stir 1 h at rt. TLC showed the reaction was complete. Thereaction was quenched by addition of the saturated aqueous NH₄Cl (800mL) at 0° C. The reaction mixture was extracted with EtOAc (1 L×3). Thecombined organic layers were washed with water and brine successively,dried over Na₂SO₄, filtered and concentrated under reduced pressure togive the crude product, which was purified by flash column on silicagel, rinsing with DCM. This solution was concentrated to obtain a solid.The orange solid was triturated with a small amount of EtOAc andfiltered, rinsing with diethyl ether to give the product (240.1 g,67.0%, three batches combined). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 13.70(s, 1H), 8.52 (dd, J=0.8, 4.8 Hz, 0.3H), 8.34 (dd, J=0.8, 5.2 Hz, 1H),8.27 (s, 0.4H), 8.10 (s, 1H), 7.47 (t, J=8.0 Hz, 1.4H), 7.22-7.12 (m,1.8H), 6.96 (s, 1.4H), 6.85 (d, J=4.2 Hz, 1H), 6.07 (s, 1H), 5.97-5.86(m, 1.4H), 5.32 (d, J=15.6 Hz, 1.4H), 5.24 (d, J=6.4 Hz, 1.4H), 4.64 (d,J=6.0 Hz, 2.8H), 4.38 (d, J=2.8 Hz, 0.8H).

Intermediate 21 2-Propen-1-yl{3-[5-(2-chloro-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}carbamate

2-Propen-1-yl{3-[(2-chloro-4-pyrimidinyl)acetyl]-2-fluorophenyl}carbamate (10 g, 28.6mmol) and N,N-dimethylacetamide (50 mL) were combined and treated withrecrystallized NBS (5.11 g, 28.7 mmol). The reaction mixture was stirredat rt for 15 min then added 2-methylpropanethioamide (3.54 g, 34.3mmol). The reaction mixture was heated to 55° C. for 30 min then pouredinto 500 mL of water. The water was decanted off and dissolved solidresidue in EtOAc. The residue was added to the EtOAc solution,concentrated and purified on silica gel [100% DCM to 60% (3:1DCM:EtOAc)]. The combined clean fractions were diluted with water andextracted three times with EtOAc. The combined EtOAc layers were driedover Na₂SO₄, filtered, concentrated and put on vacuum pump overnight.The combined unclean fractions from the first column and the residuefrom the water extractions were concentrated onto silica gel. Theresidue was purified by silica gel chromatography eluting with 100% DCMto 60% (3:1 DCM:EtOAc). The combined clean fractions from bothchromatography and initial workup were triturated in diethyl ether andfiltered to obtain a beige solid (2.1 g). The diethyl ether filtrate wasconcentrated and triturated with EtOH and filtered to obtain a yellowsolid (1.3 g). The EtOH filtrate was concentrated and triturated againin diethyl ether and filtered to obtain a light yellow solid (1.0 g).The three batches afforded 4.4 g of the title compound (35% yield). ¹HNMR (400 MHz, DMSO-d₆) δ ppm 9.50 (s, 1H) 8.57 (d, J=5.4 Hz, 1H)7.72-7.87 (m, 1H) 7.20-7.36 (m, 2H) 7.00 (d, J=5.3 Hz, 1H) 5.80-6.03 (m,1H) 5.31 (dd, J=17.3, 1.1 Hz, 1H) 5.18 (dd, J=10.5, 0.9 Hz, 1H) 4.56 (d,J=5.3 Hz, 2H) 3.20-3.49 (m, 1H) 1.35 (d, J=6.9 Hz, 6H).

Intermediate 223-(5-(2-Chloropyrimidin-4-yl)-2-isopropylthiazol-4-yl)-2-fluoroaniline

To a solution of 2-propen-1-yl{3-[5-(2-chloro-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}carbamate(15 g, 34.7 mmol) in DCM (500 mL), HOAc (5 g, 83.3 mmol), Pd(PPh₃)₂Cl₂(0.5 g, 0.69 mmol) were added. Then tri-n-butyl tin hydride (15 g, 52mmol) was added dropwise to the mixture at 0° C. The mixture was stirredat rt for 30 min. The reaction was quenched by adding saturated NaHCO₃(200 mL) slowly. The two layers were separated. The aqueous layer wasextracted with DCM (1 L×2). The combined organic layers were washed withwater and brine successively, dried over Na₂SO₄, filtered andconcentrated under reduced pressure to give the crude product, which waswashed with petroleum ether (200 mL) to afford the title compound. (10.5g, 87.6% yield). ¹H NMR (400 MHz, DMSO-d6) δ ppm 8.58 (d, J=5.2 Hz, 1H),7.01-6.96 (m, 2H), 6.89-6.85 (m, 1H), 6.63-6.59 (m, 1H), 5.29 (br. s.,2H), 3.38-3.30 (m, 1H), 1.37 (d, J=6.8 Hz, 6H).

Intermediate 23 2-Propen-1-yl{3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}carbamate

To a solution of 2-propen-1-yl{3-[(2-chloro-4-pyrimidinyl)acetyl]-2-fluorophenyl}carbamate (30 g, 85.9mmol) (Intermediate 20) in DMA (300 mL), NBS (15.3 g, 85.9 mmol) wasadded. The reaction mixture was stirred at rt for 1 h. Then2,2-dimethylpropanethioamide (11.0 g, 94.5 mmol) was added at 0° C. Themixture was stirred at rt for 2 h. The mixture was poured into water andextracted with EtOAc (200 mL×3). The combined organic layers were washedwith water and brine successively, dried over Na₂SO₄, filtered andconcentrated under reduced pressure to give the crude product, which waspurified by column chromatography on silica gel (DCM:petroleum ether2:1) to afford the title compound. (11 g, 35.4% yield). ¹H NMR (400 MHz,CDCl₃) δ ppm 8.29 (d, J=5.27 Hz, 1H), 8.12-8.19 (m, 1H), 7.12-7.25 (m,2H), 6.80-6.88 (m, 2H), 5.85-5.98 (m, 1H), 5.20-5.37 (m, 2H), 4.61-4.67(m, 2H). MS (ES+): 447 [M+H]⁺.

Intermediate 243-[5-(2-Chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluoroaniline

In a round bottom flask 2-propen-1-yl{3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}carbamate(800 mg, 1.79 mmol) was dissolved in DCM (30 mL) and water (0.5 ml).Tri-n-butyltin hydride (0.480 mL, 1.79 mmol) was added followed bytetrakis(triphenylphosphine)palladium (0) (103 mg, 0.090 mmol). Thismixture was stirred 3 h at rt. By TLC all starting material is consumed.The reaction was concentrated to dryness. The crude was then dissolvedinto a small amount of DCM and injected onto a 25 g silica gel column.The column was eluted with EtOAc and hexanes. The title compound wasobtained (0.594 g, 1.47 mmol, 82% yield). ¹H NMR (400 MHz, DMSO-d₆) δppm 8.62 (d, J=5.3 Hz, 1H), 6.96-7.08 (m, 2H), 6.91 (t, J=8.2 Hz, 1H),6.64 (t, J=6.7 Hz, 1H), 5.33 (s, 2H), 1.44 (s, 9H).

Intermediate 25N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide

To a solution of3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluoroaniline(30 g, 82.8 mmol) in DCM (250 mL) was added pyridine (19.6 g, 248 mmol).The mixture was cooled to 0° C. 2,5-Difluorobenzene-1-sulfonyl chloride(17.6 g, 82.8 mmol) in DCM (20 mL) was added dropwise to the mixture.The reaction was stirred at rt overnight. Then the reaction was washedwith water (300 mL), and extracted with DCM (2×400 mL). The organiclayer was washed with brine, dried over anhydrous NaSO₄, filtrated andconcentrated under reduced pressure to give the crude product, which waspurified by column chromatography on silica gel (petroleumether:EtOAc:DCM 20:1:5) to afford the title compound (20.4 g, 45.8%yield). ¹H NMR (400 MHz, CDCl₃) δ ppm 8.26 (d, J=5.3 Hz, 1H), 7.60-7.66(m, 1H), 7.51-7.60 (m, 1H), 7.30-7.36 (m, 1H), 7.17-7.30 (m, 3H),7.07-7.17 (m, 1H), 6.68 (d, J=5.3 Hz, 1H), 1.45 (s, 9H). MS (ES+): 539[M+H]⁺.

Intermediate 26 2-Propen-1-yl{3-[5-(2-chloro-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}carbamate

To a solution of 2-propen-1-yl{3-[(2-chloro-4-pyrimidinyl)acetyl]-2-fluorophenyl}carbamate (20 g, 57mmol) (Intermediate 20) in DMA (300 mL), NBS (10.2 g, 57 mmol) wasadded. The reaction mixture was stirred at rt for 1 h. Thenmorpholine-4-carbothioamide (9.2 g, 63 mmol) was added at 0° C. Themixture was stirred at rt for 2 h. The mixture was poured into water andextracted with EtOAc (1 L×3). The combined organic layers were washedwith water and brine successively, dried over Na₂SO₄, filtered andconcentrated under reduced pressure to give the crude product, which waspurified by column chromatography on silica gel (DCM:petroleum ether2:1) to afford the title compound (20 g, 83.5% yield). ¹H NMR (400 MHz,CDCl₃) δ ppm 8.20-8.27 (m, 1H), 8.19 (d, J=5.5 Hz, 1H), 7.20-7.26 (m,1H), 7.08-7.12 (m, 1H), 6.92-6.98 (br, 1H), 6.62 (d, J=5.5 Hz, 1H),5.90-6.03 (m, 1H), 5.25-5.41 (m, 2H), 5.65-5.70 (m, 2H), 3.57-3.63 (m,4H), 3.77-3.86 (m, 4H). m/z (ES+): 476 [M+H]⁺

Intermediate 273-(5-(2-Chloropyrimidin-4-yl)-2-morpholinothiazol-4-yl)-2-fluoroaniline

To a solution of 2-propen-1-yl{3-[5-(2-chloro-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}carbamate(57 g, 120 mmol) (prepared by a process analogous to that described forIntermediate 26) in DCM (500 mL), HOAc (17.3 g, 288 mmol), Pd(PPh₃)₂Cl₂(1.68 g, 2.4 mmol) were added. Then tri-n-butyltin hydride (38.4 g, 132mmol) was added dropwise to the mixture at 0° C. The mixture was stirredat rt for 30 min. The reaction was quenched by adding saturated NaHCO₃(300 mL) slowly. The two layers were separated. The aqueous layer wasextracted with DCM (1 L×2). The combined organic layers were washed withwater and brine successively, dried over Na₂SO₄, filtered andconcentrated under reduced pressure to give the crude product, which waswashed with petroleum ether (500 mL) to afford the title compound (43 g,91.6% yield). ¹H NMR (400 MHz, CDCl₃) δ ppm 8.15 (d, J=5.5 Hz, 1H),6.95-7.07 (m, 1H), 6.83-6.92 (m, 1H), 6.74-6.80 (m, 1H), 6.70 (d, J=5.5Hz, 1H), 3.57-3.63 (m, 4H), 3.75-3.88 (m, 4H).

Intermediate 28N-{3-[5-(2-Chloro-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide

To a solution of3-(5-(2-chloropyrimidin-4-yl)-2-morpholinothiazol-4-yl)-2-fluoroaniline(35 g, 89.5 mmol) in pyridine (400 mL), 2,6-difluorobenzene-1-sulfonylchloride (20.9 g, 98.5 mmol) was added dropwise. The reaction wasstirred at rt for 2 h. Then the reaction was washed with water (400 mL),and extracted with DCM (2×400 mL). The organic layer was washed withwater, brine, dried over anhydrous NaSO₄, filtrated and concentratedunder reduced pressure to give the crude product, which was purified bycolumn chromatography on silica gel (petroleum ether:DCM 1:2) to affordthe title compound (18.5 g, 36.4% yield). ¹H NMR (400 MHz, CDCl₃) δ ppm8.03 (d, J=5.3 Hz, 1H), 7.65-7.70 (m, 1H), 7.40-7.50 (m, 1H), 7.25-7.30(br, 1H), 7.18-7.23 (m, 2H), 6.88-6.98 (m, 2H), 6.38 (d, J=5.3 Hz, 1H),3.72-3.80 (m, 4H), 3.50-3.58 (m, 4H); m/z (ES+): 568 [M+H]⁺.

Intermediate 29N-{3-[5-(2-Chloro-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide

To a solution of3-(5-(2-chloropyrimidin-4-yl)-2-morpholinothiazol-4-yl)-2-fluoroaniline(35 g, 89.5 mmol) (Intermediate 27) in pyridine (400 mL),2,5-difluorobenzene-1-sulfonyl chloride (20.9 g, 98.5 mmol) was addeddropwise. The reaction was stirred at rt for 2 h. Then the reaction waswashed with water (400 mL), and extracted with DCM (2×400 mL). Theorganic layer was washed with water, brine, dried over anhydrous NaSO₄,filtrated and concentrated under reduced pressure to give the crudeproduct, which was purified by column chromatography on silica gel(petroleum ether:DCM 1:2) to afford the title compound (22.7 g, 44.6%yield). ¹H NMR (400 MHz, DMSO-d6) δ ppm 10.75-10.83 (br, 1H), 8.32 (d,J=5.3 Hz, 1H), 7.28-7.60 (m, 6H), 6.48 (d, J=5.3 Hz, 1H), 3.65-3.80 (m,4H), 3.50-3.65 (m, 4H); m/z (ES+): 568 [M+H]⁺.

Intermediate 30 2-Propen-1-yl{3-[5-(2-chloro-4-pyrimidinyl)-2-(tetrahydro-2H-pyran-4-yl)-1,3-thiazol-4-yl]-2-fluorophenyl}carbamate

To a solution of 2-propen-1-yl{3-[(2-chloro-4-pyrimidinyl)acetyl]-2-fluorophenyl}carbamate (85 g, 243mmol) in DMA (700 mL), NBS (43.2 g, 243 mmol) was added at 0° C. Thereaction mixture was stirred at rt for 1 h. Thentetrahydro-2H-pyran-4-carbothioamide (42.3 g, 291.6 mmol) was added atrt. The mixture was stirred at 60° C. for 1.5 h. The mixture was pouredinto water and extracted with EtOAc (400 mL×3). The combined organiclayers were washed with water and brine successively, dried over Na₂SO₄,filtered and concentrated under reduced pressure to give the crudeproduct, which was purified by column chromatography on silica gel(DCM:petroleum ether 2:1) to afford the title compound. (40 g, 35%yield). ¹H NMR (400 MHz, DMSO-d6) δ ppm 9.48-9.54 (br, 1H), 8.58 (d,J=5.3 Hz, 1H), 7.76-7.83 (m, 1H), 7.23-7.32 (m, 2H), 7.02 (d, J=5.3 Hz,1H), 5.87-5.98 (m, 1H), 5.27-5.36 (m, 1H), 5.16-5.21 (m, 1H), 4.54-4.60(m, 2H), 3.87-3.94 (m, 2H), 3.41-3.50 (m, 2H), 3.27-3.37 (m, 1H),1.97-2.04 (m, 2H), 1.69-1.82 (m, 2H).

Intermediate 313-[5-(2-Chloro-4-pyrimidinyl)-2-(tetrahydro-2H-pyran-4-yl)-1,3-thiazol-4-yl]-2-fluoroaniline

To a solution of 2-propen-1-yl{3-[5-(2-chloro-4-pyrimidinyl)-2-(tetrahydro-2H-pyran-4-yl)-1,3-thiazol-4-yl]-2-fluorophenyl}carbamate(28 g, 59 mmol) in DCM (300 mL), HOAc (8.5 g, 141.6 mmol), Pd(PPh₃)₂Cl₂(0.827 g, 1.18 mmol) were added. Then tri-n-butyl tin hydride (27 g,88.5 mmol) was added dropwise to the mixture at 0° C. The mixture wasstirred at rt for 30 min. The reaction was quenched by added thesaturated NaHCO₃ (200 mL) slowly. The two layers were separated. Theaqueous layer was extracted with DCM (300 mL×2). The combined organiclayers were washed with water and brine successively, dried over Na₂SO₄,filtered and concentrated under reduced pressure to give the crudeproduct, which was washed with petroleum ether (200 mL) to afford thetitle compound, which was used to the next step directly. (22.5 g, 97.8%yield). ¹H NMR (400 MHz, CDCl₃) δ ppm 8.35 (d, J=5.3 Hz, 1H), 7.01-7.08(m, 1H), 6.98 (d, J=5.3 Hz, 1H), 6.85-6.92 (m, 1H), 6.79-6.85 (m, 1H),4.05-4.12 (m, 2H), 3.79-3.86 (br, 2H), 3.51-3.59 (m, 2H), 3.23-3.34 (m,1H), 2.07-2.15 (m, 2H), 1.89-2.01 (m, 2H).

Intermediate 32N-{3-[5-(2-Chloro-4-pyrimidinyl)-2-(tetrahydro-2H-pyran-4-yl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide

To a solution of3-[5-(2-chloro-4-pyrimidinyl)-2-(tetrahydro-2H-pyran-4-yl)-1,3-thiazol-4-yl]-2-fluoroaniline(1.24 g, 3.17 mmol) in DCM (31.7 mL) was added pyridine (0.269 mL, 3.33mmol) and 2,5-difluorobenzenesulfonyl chloride (0.448 mL, 3.33 mmol).The reaction was stirred 18 h at rt. The reaction mixture wasconcentrated onto silica gel. Purification by chromatography (5 to 100%EtOAc:DCM) afforded the title compound (1.21 g, 2.13 mmol, 67.3% yield)as an off-white solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.79 (s, 1H),8.57 (d, J=5.5 Hz, 1H), 7.37-7.67 (m, 5H), 7.32 (t, J=7.9 Hz, 1H), 6.90(d, J=5.3 Hz, 1H), 3.93 (dd, J=11.4, 2.0 Hz, 2H), 3.39-3.58 (m, 2H),3.26-3.40 (m, 1H), 1.98-2.09 (m, 2H), 1.63-1.86 (m, 2H). MS (ESI):567.06 [M+H]⁺.

Intermediate 33N-{5-[(2-Chloro-4-pyrimidinyl)acetyl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide

Step A: Ethyl 3-{[(2,6-difluorophenyl)sulfonyl]amino}-4-fluorobenzoate

To a solution of ethyl 3-amino-4-fluorobenzoate (5.47 g, 30 mmol) andpyridine (2.55 mL, 33 mmol) in DCM (150 mL) was added2,6-difluorobenzenesulfonyl chloride (4.45 mL, 33 mmol). The reactionwas stirred overnight at rt. After 16 h, the reaction mixture wasconcentrated, triturated with ether, and dried in vacuo to generate 7.87g (66% yield) of the product of Step A as a white powder. MS (ESI): 360(M+H).

Step B:N-{5-[(2-Chloro-4-pyrimidinyl)acetyl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide

To a solution of ethyl3-{[(2,6-difluorophenyl)sulfonyl]amino}-4-fluorobenzoate (5.0 g, 13.9mmol) in THF (100 mL) was added 1.0M LiHMDS in THF (34.8 mL, 34.8 mmol).A solution of 2-chloro-4-methylpyrimidine (2.7 g, 20.9 mmol) in THF (100mL) was added dropwise over 30 min, and the reaction was stirredovernight at rt. The reaction was quenched with 10 mL of MeOH andconcentrated, and the residue was partitioned between EtOAc andsaturated aqueous NaHCO₃. The aqueous layer was extracted with 2×50 mLEtOAc, and the combined organic layers were passed through a pad ofsilica gel, concentrated, and adsorbed onto silica gel. The crudeproduct was purified via flash chromatography with 0-100% EtOAc/DCM togenerate 3.07 g (50% yield) of the title compound as a white powder. MS(ESI): 443 (M+H).

Intermediate 34N-{5-[5-(2-Chloro-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide

To a solution ofN-{5-[(2-chloro-4-pyrimidinyl)acetyl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide(1.0 g, 2.3 mmol) in DMF (10 mL) was added NBS (0.49 g, 2.8 mmol). Afterstirring for 45 min at rt, 2-methylpropanethioamide (0.35 g, 3.4 mmol),was added and the reaction was stirred at rt. After 4 h, the reactionmixture was partitioned between ether and saturated aqueous NaHCO₃. Theorganic layer was washed with brine, dried over anhydrous NaSCO₄,filtered, and concentrated to generate 0.49 g (41% yield) as a yellowpowder. MS (ESI) 525 (M+H).

Intermediate 35N-{5-[(2-Chloro-4-pyrimidinyl)acetyl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide

Step A: Methyl 3-(2,5-difluorophenylsulfonamido)-4-fluorobenzoate

To a solution of methyl 3-amino-4-fluorobenzoate (25 g, 149 mmol) in DCM(150 mL) were added pyridine (35.3 g, 446 mmol) and a catalytic amountof DMAP (1.8 g, 14.9 mmol). The mixture was cooled to 0° C.2,5-Difluorobenzene-1-sulfonyl chloride (34.7 g, 212 mmol) in DCM (20mL) was added dropwise to the mixture. The reaction was stirred at rtovernight. Then the reaction was washed with water (300 mL), andextracted with DCM (2×400 mL). The organic layer was washed with brine,dried over anhydrous NaSO₄, filtrated and concentrated under reducedpressure to give the crude product, which was washed with petroleumether to afford the title compound of Step A (48.2 g, 94.5% yield). ¹HNMR (400 MHz, CDCl₃) δ ppm 8.12-8.18 (m, 1H), 7.73-7.80 (m, 1H),7.47-7.53 (m, 1H), 7.10-7.25 (m, 1H), 7.00-7.07 (m, 1H), 3.86 (s, 3H).

Step B:N-(5-(2-(2-Chloropyrimidin-4-yl)acetyl)-2-fluorophenyl)-2,5-difluorobenzenesulfonamide

To a solution of methyl3-(2,5-difluorophenylsulfonamido)-4-fluorobenzoate (40 g, 116 mmol) indry THF (500 mL) at −10° C., LiHMDS (1M in THF, 406 mmol, 406 mL) wasadded dropwise and the solution was allowed to stir for 1 h at 0° C. Asolution of 2-chloro-4-methylpyrimidine (17.8 g, 139 mmol) in THF (50mL) was then added dropwise to the solution of ester and base at 0° C.over 20 min. The solution was allowed to stir 1 h at rt. TLC showed thereaction was complete. The reaction was quenched by addition of thesaturated aqueous NH₄Cl (300 mL) at 0° C. The reaction mixture wasextracted with EtOAc (500 mL×3). The combined organic layers were washedwith water and brine successively, dried over Na₂SO₄, filtered andconcentrated under reduced pressure to give the crude product, which waspurified by flash column on silica gel, eluting with DCM. This solutionwas evaporated to obtain a solid. The orange solid was triturated with asmall amount of EtOAc and filtered, rinsing with diethyl ether to givethe title compound of Step B (31 g, 60.8% yield). ¹H NMR (400 MHz,CDCl₃) δ ppm 13.72-13.77 (br, 1H), 8.57-8.61 (m, 0.4H), 8.38-8.42 (m,1H), 8.13-8.19 (m, 0.4H), 7.97-8.02 (m, 1H), 7.78-7.82 (m, 0.4H),7.57-7.63 (m, 1H), 7.52-7.57 (1.4H), 7.02-7.30 (m, 4.2H), 6.91-6.93 (m,1H), 5.93 (s, 1H), 4.40 (s, 1H). MS (ES+): 442 [M+H]⁺.

Intermediate 36N-{5-[5-(2-Chloro-4-pyrimidinyl)-2-(tetrahydro-2H-pyran-4-yl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide

To a solution ofN-{5-[(2-chloro-4-pyrimidinyl)acetyl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide(0.910 g, 2.06 mmol) (prepared in a manner analogous to Intermediate 35)in DMA (8.24 mL) was added NBS (0.385 g, 2.16 mmol). The reactionstirred 30 min at rt and then tetrahydro-2H-pyran-4-carbothioamide(0.389 g, 2.68 mmol) was added. The reaction stirred 16 h at rt. Thereaction mixture was poured into water (150 mL), causing precipitationof a solid. The solid was collected by vacuum filtration, redissolved inEtOAc (50 mL), and concentrated onto silica gel. Purification bychromatography (20 to 100% EtOAc:hexanes) afforded the title compound(690 mg, 1.21 mmol, 58.5% yield) as a yellow solid. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 10.86 (s, 1H), 8.58 (d, J=5.3 Hz, 1H), 7.45-7.69 (m, 4H),7.42 (dd, J=7.5, 2.0 Hz, 1H), 7.32 (dd, J=10.1, 8.8 Hz, 1H), 7.14 (d,J=5.3 Hz, 1H), 3.95 (dd, J=11.7, 2.0 Hz, 2H), 3.40-3.56 (m, 2H),3.25-3.41 (m, 1H), 2.02 (dd, J=12.9, 1.6 Hz, 2H), 1.65-1.86 (m, 2H). MS(ESI): 567.09 [M+H]⁺.

Intermediate 37 2-Propen-1-yl{5-[(2-chloro-4-pyrimidinyl)acetyl]-2-fluorophenyl}carbamate

Step A: Methyl 4-fluoro-3-{[(2-propen-1-yloxy)carbonyl]amino}benzoate

To a solution of methyl 3-amino-4-fluorobenzoate (109 g, 644 mmol) inTHF (2000 mL), saturated NaHCO₃ (68 g, 805 mmol) was added. Then2-propen-1-yl chloridocarbonate (93 g, 773 mmol) was added dropwise at0° C. The mixture was stirred at rt for 2 h. The solution was extractedwith EtOAc (500 mL×3). The combined organic layers were washed withwater and brine successively, dried over Na₂SO₄, filtered andconcentrated under reduced pressure to give the crude product (160 g,98%), which was used in the next step directly. ¹H NMR (400 MHz, CDCl₃)δ ppm 8.72-8.81 (m, 1H), 7.71-7.79 (m, 1H), 7.09-7.16 (m, 1H), 6.87-6.94(br, 1H), 5.91-6.03 (m, 1H), 5.41 (d, J=17.1 Hz, 1H), 5.28 (d, J=10.5,1H), 4.70 (d, J=10.5 Hz, 1H), 4.70 (d, J=5.5 Hz, 2H), 3.90 (s, 3H).

Step B: 2-Propen-1-yl{5-[(2-chloro-4-pyrimidinyl)acetyl]-2-fluorophenyl}carbamate

To a solution of methyl4-fluoro-3-{[(2-propen-1-yloxy)carbonyl]amino}benzoate (60 g, 237 mmol)in dry THF (500 mL) at −10° C., LiHMDS (1M in THF, 735 mmol, 735 mL) wasadded dropwise and the solution was allowed to stir for 1 h at 0° C. Asolution of 2-chloro-4-methylpyrimidine (30.5 g, 237 mmol) in THF (50mL) was then added dropwise to the solution of ester and base at 0° C.over 20 min. The solution was allowed to stir 1 h at rt. TLC showed thereaction was complete. The reaction was quenched by addition of thesaturated aqueous NH₄Cl (200 mL) at 0° C. The reaction mixture wasextracted with EtOAc (500 mL×3). The combined organic layers were washedwith water and brine successively, dried over Na₂SO₄, filtered andconcentrated under reduced pressure to give the crude product, which waspurified by flash column on silica gel, eluting with DCM. This solutionwas evaporated to obtain a solid. The orange solid was triturated with asmall amount of EtOAc and filtered, rinsing with diethyl ether to givethe title compound (69.8 g, 81.6% yield). ¹H NMR (400 MHz, CDCl₃) δ ppm13.66 (br, 0.55H), 8.79-8.83 (m, 0.36H), 8.53-8.61 (m, 0.91H), 8.33-8.37(m, 0.59H), 7.65-7.72 (m, 0.40H), 7.50-7.57 (m, 0.59H), 7.26-7.30 (m,0.35H), 7.08-7.19 (m, 1H), 6.92-7.12 (br, 1H), 6.87-6.92 (m, 0.64H),5.90-6.21 (m, 1.5H), 5.39 (d, J=18.1 Hz, 1H), 5.29 (d, J=10.4 Hz, 1H),4.70 (d, J=5.5 Hz, 2H), 4.44 (s, 1H).

Intermediate 38 2-Propen-1-yl{5-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}carbamate

To a solution of 2-propen-1-yl{5-[(2-chloro-4-pyrimidinyl)acetyl]-2-fluorophenyl}carbamate (35 g,100.3 mmol in DMA, 500 mL), NBS (17.8 g, 100.3 mmol) was added. Thereaction mixture was stirred at rt for 1 h. Then2,2-dimethylpropanethioamide (13 g, 111 mmol) was added at 0° C. Themixture was stirred at 80° C. for 2 h. The mixture was poured into waterand extracted with EtOAc (1 L×3). The combined organic layers werewashed with water and brine successively, dried over Na₂SO₄, filteredand concentrated under reduced pressure to give the crude product, whichwas purified by column chromatography on silica gel (DCM:petroleum ether2:1) to afford the title compound (36 g, 80.5% yield). ¹H NMR (400 MHz,CDCl₃) δ ppm 8.24-8.31 (m, 2H), 7.09-7.18 (m, 2H), 7.01 (d, J=5.5 Hz,1H), 6.92-6.98 (br, 1H), 5.87-5.97 (m, 1H), 5.31-5.37 (m, 1H), 5.24-5.28(m, 1H), 4.61-4.65 (m, 2H), 1.46 (s, 9H).

Intermediate 395-[5-(2-Chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluoroaniline

To a solution of 2-propen-1-yl{5-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}carbamate(35 g, 78.4 mmol) in DCM (400 mL), HOAc (11.3 g, 188 mmol), Pd(PPh₃)₂Cl₂(1.1 g, 1.57 mmol) were added. Then tri-n-butyl tin hydride (34.2 g, 117mmol) was added dropwise to the mixture at 0° C. The mixture was stirredat rt for 30 min. The reaction was quenched by added the saturatedNaHCO₃ (400 mL) slowly. The two layers were separated. The aqueous layerwas extracted with DCM (500 mL×2). The combined organic layers werewashed with water and brine successively, dried over Na₂SO₄, filteredand concentrated under reduced pressure to give the crude product, whichwas washed with petroleum ether (200 mL) to afford the title compound(18.3 g, 64.4% yield). ¹H NMR (400 MHz, CDCl₃) δ ppm 8.31 (d, J=5.5 Hz,1H), 6.96-7.03 (m, 3H), 6.78-6.83 (m, 1H), 2.30-2.60 (br, 2H), 1.48 (s,9H).

Intermediate 40N-{5-[5-(2-Chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide

To a solution of5-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluoroaniline(13 g, 36 mmol) in DCM (100 mL) was added pyridine (8.5 g, 107 mmol).The mixture was cooled to 0° C. 2,6-Difluorobenzene-1-sulfonyl chloride(9.1 g, 43 mmol) in DCM (20 mL) was added dropwise to the mixture. Thereaction was stirred at rt over night. Then the reaction was washed withwater (100 mL), and extracted with DCM (2×200 mL). The organic layer waswashed with brine, dried over anhydrous NaSO₄, filtrated andconcentrated under reduced pressure to give the crude product, which waspurified by column chromatography on silica gel (petroleum ether:DCM1:2) to afford the title compound (12 g, 62.2% yield, two batchescombined). ¹H NMR (400 MHz, DMSO-d6) δ ppm 10.95-11.05 (br, 1H), 8.54(d, J=5.2 Hz, 1H), 7.67-7.79 (m, 1H), 7.45-7.50 (m, 2H), 7.22-7.37 (m,3H), 7.10 (d, J=5.2 Hz, 1H), 1.42 (s, 9H). MS (ES+): 539 [M+H]⁺.

Intermediate 41 2-Propen-1-yl{5-[5-(2-chloro-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}carbamate

In a procedure analogous to Intermediate 6, 1.5 g (43% yield) of2-propen-1-yl{5-[5-(2-chloro-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}carbamatewas prepared from 2-propen-1-yl{5-[(2-chloro-4-pyrimidinyl)acetyl]-2-fluorophenyl}carbamate (2.8 g, 8mmol) (Intermediate 37). MS (ESI): 432.82 (M+H)⁺.

Intermediate 425-[5-(2-Chloro-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]-2-fluoroaniline

In a procedure analogous to Intermediate 13, 1.1 g (92% yield) of thetitle compound was prepared from 2-propen-1-yl{5-[5-(2-chloro-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}carbamate(1.5 g, 3.5 mmol) (Intermediate 41). MS (ES+) MS: 349.27 (M+H)⁺.

Intermediate 43N-{5-[5-(2-Chloro-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide

In a procedure analogous to Intermediate 14 using5-[5-(2-chloro-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]-2-fluoroaniline(23 g, 66.1 mmol) and 2,5-difluorobenzene-1-sulfonyl chloride (15.4 g,72.7 mmol) the title compound was obtained (19.6 g, 62.2% yield). ¹H NMR(400 MHz, CDCl₃) δ ppm 8.32 (d, J=5.3 Hz, 1H), 7.62 (dd, J=2.2, 7.7 Hz,1H), 7.44-7.49 (m, 1H), 7.34-7.37 (br, 1H), 7.14-7.34 (m, 3H), 7.08 (dd,J=8.4, 9.7 Hz, 1H), 6.92 (d, J=5.3 Hz, 1H), 3.32 (m, 1H), 1.44 (d, J=6.8Hz, 6H). MS (ES+): 525 [M+H]⁺.

Intermediate 44N-{2-Chloro-3-[(E)-2-(2-chloro-4-pyrimidinyl)-1-hydroxyethenyl]phenyl}-2,6-difluorobenzenesulfonamide

Step A: Methyl 2-chloro-3-nitrobenzoate

To a suspension of 2-chloro-3-nitrobenzoic acid (100 g, 495 mmol) inMeOH (600 mL) was added TsOH (20 g, 10%). Then the mixture was heated atreflux overnight. The solvent was removed. The residue was diluted withEtOAc (1 L). Then the pH was adjusted to around 9 by progressivelyadding saturated NaHCO₃. The organic layer was separated. The aqueouslayer was extracted with EtOAc (1 L×3). The combined organic layers werewashed with water and brine successively, dried over Na₂SO₄, filteredand concentrated under reduced pressure to give the title compound (96g, 90.6% yield). ¹H NMR (400 MHz, CDCl₃) δ ppm 7.90 (dd, J=1.8 Hz, 7.9Hz, 1H), 7.81 (dd, J=1.5 Hz, 7.7 Hz, 1H), 7.45 (dd, J=7.7 Hz, 7.9 Hz,1H), 3.94 (s, 1H).

Step B: Methyl 3-amino-2-chlorobenzoate

To a solution of methyl 2-chloro-3-nitrobenzoate (25 g, 116 mmol) inMeOH (150 mL) was added Raney Ni (3 g). The mixture was stirred under H₂atmosphere (50 psi at 25° C.) for 3.5 h. The catalyst was filtered, andthe filtrate was concentrated under the reduced pressure to dryness togive the crude product, which was purified by recrystallization in EtOActo afford the title compound (69 g, 83.5% yield, four batches combined).¹H NMR (400 MHz, CDCl₃) δ ppm 6.70-7.25 (m, 3H), 4.40-4.50 (br, 2H),3.87 (s, 3H).

Step C: Methyl 2-chloro-3-(2,6-difluorophenylsulfonamido)benzoate

Following a procedure analogous to Intermediate 5, Step A using methyl3-amino-2-chlorobenzoate (39 g, 211 mmol) in DCM (200 mL) was addedpyridine (51 g, 633 mmol) and 2,6-difluorobenzene-1-sulfonyl chloride(49.1 g, 232 mmol) the title compound was obtained (62 g, 81.6% yield).¹H NMR (400 MHz, CDCl₃) δ ppm 7.87 (dd, J=1.8 Hz, 8.38 Hz, 1H),7.72-7.79 (br, 1H), 7.56 (dd, J=1.8 Hz, 7.94 Hz, 1H), 7.45-7.53 (m, 1H),7.28 (dd, J=7.9 Hz, 8.4 Hz, 1H), 6.95-7.01 (m, 2H), 3.89 (s, 3H).

Step D:N-{2-chloro-3-[(E)-2-(2-chloro-4-pyrimidinyl)-1-hydroxyethenyl]phenyl}-2,6-difluorobenzenesulfonamide

Following a procedure analogous to Intermediate 5, Step B using methyl2-chloro-3-(2,6-difluorophenylsulfonamido)benzoate (31 g, 85.9 mmol) and2-chloro-4-methylpyrimidine (12.2 g, 94.5 mmol) the title compound wasobtained (33 g, 73.5% yield). ¹H NMR (400 MHz, CDCl₃) δ ppm 13.47-13.52(br, 0.96H), 8.50-8.56 (m, 0.13H), 8.38 (d, J=5.3 Hz, 1H), 7.78-7.82 (m,0.15H), 7.62-7.73 (m, 2H), 7.40-7.50 (m, 1.18H), 7.17-7.30 (m, 1.77H),6.90-6.97 (m, 2.29H), 6.83 (d, J=5.3 Hz, 1H), 5.65 (s, 1H), 4.28 (s,0.26H). MS (ES+): 458 [M+H]⁺.

Intermediate 45N-{2-Chloro-3-[(E)-2-(2-chloro-4-pyrimidinyl)-1-hydroxyethenyl]phenyl}-2,5-difluorobenzenesulfonamide

To a solution of methyl 3-amino-2-chlorobenzoate (16.3 g, 88 mmol) inpyridine (150 mL) was added 2,5-difluorobenzenesulfonyl chloride (13.0ml, 97 mmol) dropwise. The solution was stirred at rt overnight. Thecrude reaction mixture was concentrated by about half, and ˜200 mL ofwater was added. A red oil precipitated from the mixture. The oil wasseparated, and crystallized upon standing. The crystals were collectedby vacuum filtration, washed with ether, and dried in vacuo to generate16.8 g (46.4 mmol, 52.8% yield) as a white powder. LC/MS indicates thatthe product is a ˜2:1 mixture of the desired product and thebis-sulfonamide. The white powder was dissolved in THF (100 mL), and a1M solution of LiHMDS in THF (100 mL, 100 mmol) was added. A solution of2-chloro-4-methylpyrimidine (8.0 g, 62.2 mmol) in THF (10 mL) was addeddropwise over 15 minutes. The solution was stirred at 20° C. for anadditional 20 minutes, and then the reaction was quenched with MeOH (5mL). The solvent was removed with a rotary evaporator, and the residuewas partitioned between EtOAc and water. The aqueous layer was acidifiedto pH<9 with saturated aqueous ammonium chloride, and extracted withEtOAc. The combined organic layers were dried over anhydrous NaSO₄,filtered, and concentrated to ˜50 mL. The brown solution was passedthrough a pad of silica gel (eluting with EtOAc) and concentrated togenerate the title compound (6.78 g, 14.8 mmol, 16.8% yield) as a yellowpowder. MS (ESI): 458.0 [M+H]+.

Example 12,6-Difluoro-N-{3-[2-(1-methylethyl)-5-(2-{[2-(methylsulfonyl)ethyl)]amino}-4-pyrimidinyl)-1,3-thiazol-4-yl]phenyl}benzenesulfonamide

A neat mixture ofN-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]phenyl}-2,6-difluorobenzenesulfonamide(0.15 g, 0.30 mmol) and 2-aminoethyl-methyl-sulfone (0.20 g, 1.62 mmol)was heated at 60° C. overnight. The reaction mixture was diluted with 1MHCl and extracted with DCM twice. The organic layer was dried over MgSO₄and evaporated onto silica gel. Purification by ISCO chromatography (0to 40% 1:9 MeOH:EtOAC in DCM) afforded the title compound (74 mg, 40.0%yield) as a white solid. ¹H NMR (400 MHz, DMSO-d6) δ ppm 11.04 (s, 1H),8.06 (d, J=5.1 Hz, 1H), 7.65-7.75 (m, 1H), 7.46 (t, J=5.7 Hz, 1H), 7.35(t, J=7.9 Hz, 1H), 7.16-7.30 (m, 5H), 6.09 (br. s., 1H), 3.60-3.73 (m,2H), 3.34-3.38 (m, 2H), 3.25-3.30 (m, 1H), 3.02 (s, 3H), 1.36 (d, J=6.9Hz, 6H). MS (ESI): 594.2 [M+H]⁺.

Example 2N-{3-[2-(1,1-Dimethylethyl)-5-(2-{[2-(methylsulfonyl)ethyl]amino}-4-pyrimidinyl)-1,3-thiazol-4-yl]phenyl}-2,6-difluorobenzenesulfonamide

Following a procedure analogous to that described in Example 1 usingN-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]phenyl}-2,6-difluorobenzenesulfonamide(0.08 g, 0.15 mmol), 42 mg (43% yield) of the title compound wasobtained. ¹H NMR (400 MHz, DMSO-d6) δ ppm 11.05 (s, 1H), 8.06 (d, J=5.1Hz, 1H), 7.65-7.77 (m, 1H), 7.45 (t, J=5.7 Hz, 1H), 7.35 (t, J=7.9 Hz,1H), 7.16-7.31 (m, 5H), 6.06-6.20 (m, 1H), 3.59-3.74 (m, 2H), 3.33-3.40(m, 2H), 3.02 (s, 3H), 1.42 (s, 9H). MS (ESI): 608.2 [M+H]⁺.

Example 3N-[3-(2-(1,1-Dimethylethyl)-5-{2-[(2-methylpropyl)amino]-4-pyrimidinyl}-1,3-thiazol-4-yl)phenyl]-2,5-difluorobenzenesulfonamide

A suspension ofN-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]phenyl}-2,5-difluorobenzenesulfonamide(150 mg, 0.288 mmol) and isobutylamine (1 mL, 10.06 mmol) was stirred atrt overnight. The reaction mixture was diluted with DCM and washed withdilute aqueous HCl. The DCM extract was dried over MgSO₄, filtered,evaporated onto silica gel and chromatographed (0-20% MeOH in DCM). Thetitle compound was obtained as a yellow solid (75 mg, 44% yield). ¹H NMR(400 MHz, DMSO-d6) δ ppm 10.87 (s, 1H), 7.96 (d, J=5.2 Hz, 1H),7.40-7.62 (m, 3H), 7.23-7.33 (m, 2H), 7.20 (s, 1H), 7.14 (d, J=7.7 Hz,2H), 6.00 (br. s., 1H), 2.85-3.11 (m, 2H), 1.67-1.87 (m, 1H), 1.36 (s,9H), 0.82 (d, J=6.4 Hz, 6H). MS (ESI): 558.0 [M+H]⁺.

Example 4N-{5-[5-(2-{[2-(Ethyloxy)ethyl]amino}-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide

Following a procedure analogous to the procedure described in Example 1usingN-{5-[5-(2-chloro-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide(0.150 g, 0.286 mmol) and 2-ethoxyethylamine (0.5 mL, 4.77 mmol), thetitle compound was obtained (64 mg, 36% yield). ¹H NMR (400 MHz,DMSO-d6) δ ppm 10.92 (s, 1H), 8.08 (d, J=5.1 Hz, 1H), 7.66-7.77 (m, 1H),7.36-7.46 (m, 2H), 7.20-7.32 (m, 4H), 6.19 (s, 1H), 3.35-3.51 (m, 6H),3.24-3.30 (m, 1H), 1.36 (d, J=6.9 Hz, 6H), 1.10 (q, J=6.7 Hz, 3H). MS(ESI): 578.2 [M+H]⁺.

Example 52,6-Difluoro-N-[2-fluoro-5-(2-(1-methylethyl)-5-{2-[(tetrahydro-2-furanylmethyl)amino]-4-pyrimidinyl}-1,3-thiazol-4-yl)phenyl]benzenesulfonamide

Following a procedure analogous to the procedure described in Example 1usingN-{5-[5-(2-chloro-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide(0.150 g, 0.286 mmol) and tetrahydrofufurylamine (0.5 mL, 4.84 mmol),the title compound was obtained as a white solid (71 mg, 41% yield). ¹HNMR (400 MHz, DMSO-d6) δ ppm 10.93 (s, 1H), 8.08 (d, J=5.1 Hz, 1H),7.67-7.76 (m, 1H), 7.43 (dd, J=7.6, 2.2 Hz, 1H), 7.37-7.41 (m, 1H),7.23-7.32 (m, 4H), 6.19 (br. s., 1H), 3.93-4.01 (m, 1H), 3.72-3.80 (m,1H), 3.57-3.65 (m, 1H), 3.35-3.41 (m, 1H), 3.26-3.32 (m, 2H), 1.74-1.93(m, 3H), 1.51-1.62 (m, 1H), 1.36 (d, J=6.9 Hz, 6H). MS (ESI): 590.2[M+H]⁺.

Example 6N-{5-[5-{2-[(Cyclopropylmethyl)amino]-4-pyrimidinyl}-2-(1-methylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide

Following a procedure analogous to the procedure described in Example 1usingN-{5-[5-(2-chloro-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide(60 mg, 0.11 mmol) and 1-cyclopropylmethanamine (0.1 mL, approx. 1.4mmol) the title compound was obtained as an off-white solid (25 mg, 39%yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.90 (s, 1H), 8.05 (d, J=5.1Hz, 1H), 7.59-7.79 (m, 1H), 7.33-7.44 (m, 3H), 7.20-7.29 (m, 3H), 6.15(br. s., 1H), 3.00-3.15 (m, 2H), 2.42-2.45 (m, 1H), 1.34 (d, J=7.0 Hz,6H), 0.94-1.06 (m, 1H), 0.34-0.42 (m, 2H), 0.16-0.22 (m, 2H). MS (ESI):560.1 [M+H]⁺.

Example 72,6-Difluoro-N-{2-fluoro-5-[2-(1-methylethyl)-5-(2-{[3-(4-morpholinyl)propyl]amino}-4-pyrimidinyl)-1,3-thiazol-4-yl]phenyl}benzenesulfonamide

Following a procedure analogous to the procedure described in Example 1usingN-{5-[5-(2-chloro-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide(80 mg, 0.15 mmol) and 3-(4-morpholinyl)-1-propanamine (0.10 mL, approx.6.9 mmol) the title compound was obtained as a white solid (85 mg, 89%yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.01 (d, J=5.1 Hz, 1H),7.52-7.67 (m, 1H), 7.36 (dd, J=7.6, 1.6 Hz, 1H), 7.21-7.32 (m, 2H),7.07-7.21 (m, 3H), 6.14 (br. s., 1H), 3.57 (br. s., 4H), 3.20-3.36 (m,8H), 2.36-2.41 (m, 1H), 1.65 (br. s., 2H), 1.31 (d, J=6.8 Hz, 6H). MS(ESI): 633.5 [M+H]⁺.

Example 82,6-Difluoro-N-{2-fluoro-5-[2-(1-methylethyl)-5-(2-{[2-(methylsulfonyl)ethyl]amino}-4-pyrimidinyl)-1,3-thiazol-4-yl]phenyl}benzenesulfonamide

Following a procedure analogous to the procedure described in Example 1usingN-{5-[5-(2-chloro-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide(3.0 g, 5.71 mmol) and 2-aminoethyl-methyl-sulfone (2.82 g, 22.86 mmol),the title compound was obtained as a white solid (1.9 g, 53% yield). ¹HNMR (400 MHz, DMSO-d6) δ ppm 10.93 (s, 1H), 8.14 (d, J=5.0 Hz, 1H),7.67-7.77 (m, 1H), 7.48 (t, J=5.5 Hz, 1H), 7.38-7.46 (m, 2H), 7.28 (q,J=9.2 Hz, 3H), 6.22-6.31 (m, 1H), 3.62-3.73 (m, 2H), 3.34-3.40 (m, 2H),3.25-3.30 (m, 1H), 3.02 (s, 3H), 1.36 (d, J=6.9 Hz, 6H). MS (ESI): 612.2[M+H]⁺.

Example 9N-{5-[5-[2-(Ethylamino)-4-pyrimidinyl]-2-(1-methylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide

Following a procedure analogous to the procedure described in Example 1usingN-{5-[5-(2-chloro-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide(0.150 g, 0.286 mmol) and ethyl amine 2.0M in THF (2 mL, 4.00 mmol), thetitle compound was obtained as an off-white solid (74 mg, 49% yield). ¹HNMR (400 MHz, DMSO-d6) δ ppm 10.92 (s, 1H), 8.07 (d, J=5.0 Hz, 1H),7.65-7.80 (m, 1H), 7.44 (dd, J=7.5, 1.8 Hz, 1H), 7.36-7.42 (m, 1H),7.21-7.33 (m, 4H), 6.17 (br. s., 1H), 3.16-3.31 (m, 3H), 1.36 (d, J=6.9Hz, 6H), 1.10 (t, J=7.1 Hz, 3H). MS (ESI): 534.2 [M+H]⁺.

Example 10N-{5-[2-(1,1-Dimethylethyl)-5-(2-{[2-(methylsulfonyl)ethyl]amino}-4-pyrimidinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide

Following a procedure analogous to the procedure described in Example 1usingN-{5-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide(0.149 g, 0.276 mmol) and 2-aminoethyl-methyl-sulfone (0.3 g, 2.4 mmol),the title compound was obtained as a white solid (75 mg, 43% yield). ¹HNMR (400 MHz, DMSO-d6) δ ppm 10.95 (s, 1H), 8.14 (d, J=5.0 Hz, 1H),7.65-7.79 (m, 1H), 7.36-7.53 (m, 3H), 7.22-7.34 (m, 3H), 6.28 (br. s.,1H), 3.60-3.75 (m, 2H), 3.35-3.40 (m, 2H), 3.02 (s, 3H), 1.42 (s, 9H).MS (ESI): 626.2 [M+H]⁺.

Example 112,6-Difluoro-N-{2-fluoro-3-[2-(1-methylethyl)-5-(2-{[2-(methylsulfonyl)ethyl]amino}-4-pyrimidinyl)-1,3-thiazol-4-yl]phenyl}benzenesulfonamide

Following a procedure analogous to the procedure described in Example 1usingN-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide(0.100 g, 0.190 mmol) and 2-aminoethyl-methyl-sulfone (0.100 g, 0.812mmol), the title compound was obtained as an off-white solid (53 mg, 43%yield). ¹H NMR (400 MHz, DMSO-d6) δ ppm 10.87 (s, 1H), 8.09 (d, J=5.1Hz, 1H), 7.62-7.74 (m, 1H), 7.39-7.49 (m, 2H), 7.33-7.39 (m, 1H),7.20-7.32 (m, 3H), 5.89-6.05 (m, 1H), 3.63 (br. s., 2H), 3.34-3.39 (m,2H), 3.25-3.31 (m, 1H), 2.99-3.04 (m, 3H), 1.35 (d, J=6.9 Hz, 6H). MS(ESI): 613.2 [M+H]⁺.

Example 12N-{3-[2-(1,1-Dimethylethyl)-5-(2-{[3-(methylsulfonyl)propyl]amino}-4-pyrimidinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide

Step A:N-{3-[2-(1,1-Dimethylethyl)-5-(2-{[3-(methylthio)propyl]amino}-4-pyrimidinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide

Following a procedure analogous to the procedure described in Example 1usingN-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide(110 mg, 0.204 mmol) and [3-(methylthio)propyl]amine (200 mg, 1.90 mmol)the title compound of Step A was obtained (124 mg, 90% yield). MS (ESI):608.1 [M+H]⁺.

Step B:N-{3-[2-(1,1-Dimethylethyl)-5-(2-{[3-(methylsulfonyl)propyl]amino}-4-pyrimidinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide

To a solution of oxone (376 mg, 0.612 mmol) in water (5 mL) at 0° C., asolution ofN-{3-[2-(1,1-dimethylethyl)-5-(2-{[3-(methylthio)propyl]amino}-4-pyrimidinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide(124 mg, 0.204 mmol) in 90% EtOH (10 mL) was added dropwise. Thesolution was allowed to stir at rt for 1 hr. The reaction mixture wasdiluted with EtOAc and washed with water. The organic layer was driedover MgSO₄, filtered, evaporated onto silica gel and chromatographed(0-40% 1:9 MeOH:EtOAc in DCM). The title compound was obtained as awhite solid (30 mg, 22% yield). ¹H NMR (400 MHz, DMSO-d6) δ ppm 10.88(s, 1H), 8.04 (d, J=5.2 Hz, 1H), 7.58-7.77 (m, 2H), 7.32-7.51 (m, 2H),7.13-7.34 (m, 3H), 5.87-6.07 (m, 1H), 3.19-3.30 (m, 2H), 3.08-3.18 (m,2H), 2.97 (s, 3H), 1.82-2.01 (m, 2H), 1.40 (s, 9H). MS (ESI): 640.2[M+H]⁺.

Example 13N-[3-(2-(1,1-Dimethylethyl)-5-{2-[(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)amino]-4-pyrimidinyl}-1,3-thiazol-4-yl)-2-fluorophenyl]-2,6-difluorobenzenesulfonamide

Step A:N-(3-{2-(1,1-Dimethylethyl)-5-[2-(tetrahydro-2H-thiopyran-4-ylamino)-4-pyrimidinyl]-1,3-thiazol-4-yl}-2-fluorophenyl)-2,6-difluorobenzenesulfonamide

Following a procedure analogous to the procedure described in Example 1usingN-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide(100 mg, 0.186 mmol) and tetrahydro-2H-thiopyran-4-amine (100 mg, 0.853mmol) the title compound was obtained as a crude yellow foam and useddirectly in the next step. MS (ESI): 620.2 [M+H]⁺.

Step B:N-[3-(2-(1,1-Dimethylethyl)-5-{2-[(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)amino]-4-pyrimidinyl}-1,3-thiazol-4-yl)-2-fluorophenyl]-2,6-difluorobenzenesulfonamide

Following a procedure analogous to the procedure described in Example12, Step B using crudeN-(3-{2-(1,1-dimethylethyl)-5-[2-(tetrahydro-2H-thiopyran-4-ylamino)-4-pyrimidinyl]-1,3-thiazol-4-yl}-2-fluorophenyl)-2,6-difluorobenzenesulfonamideand oxone (342 mg, 0.557 mmol), the title compound was obtained as anoff-white solid (30 mg, 24% yield over 2 steps). ¹H NMR (400 MHz,DMSO-d6) δ ppm 10.88 (s, 1H), 8.08 (d, J=5.1 Hz, 1H), 7.60-7.75 (m, 1H),7.48 (d, J=7.4 Hz, 1H), 7.32-7.44 (m, 2H), 7.28 (t, J=7.9 Hz, 1H), 7.23(t, J=9.1 Hz, 2H), 6.01 (br. s., 1H), 3.07-3.24 (m, 4H), 1.91-2.19 (m,5H), 1.41 (s, 9H). MS (ESI): 652.1 [M+H]⁺.

Example 142,6-Difluoro-N-{2-fluoro-3-[5-(2-{[2-(methylsulfonyl)ethyl]amino}-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]phenyl}benzenesulfonamide

Following a procedure analogous to the procedure described in Example 1usingN-{3-[5-(2-chloro-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide(0.101 g, 0.178 mmol) and 2-aminoethyl-methyl-sulfone (0.30 g, 2.436mmol) the title compound was obtained as a yellow solid (72 mg, 61%yield). ¹H NMR (400 MHz, DMSO-d6) δ ppm 10.87 (s, 1H), 7.93 (d, J=5.3Hz, 1H), 7.62-7.75 (m, 1H), 7.36-7.51 (m, 1H), 7.17-7.36 (m, 5H), 5.72(d, J=5.3 Hz, 1H), 3.71 (t, J=4.6 Hz, 4H), 3.59-3.68 (m, 2H), 3.46 (t,J=4.6 Hz, 4H), 3.34 (s, 2H), 3.02 (s, 3H). MS (ESI): 655.2 [M+H]⁺.

Example 152,6-Difluoro-N-{2-fluoro-3-[5-(2-{[3-(methylsulfonyl)propyl]amino}-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]phenyl}benzenesulfonamide

Step A:2,6-Difluoro-N-{2-fluoro-3-[5-(2-{[3-(methylthio)propyl]amino}-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]phenyl}benzenesulfonamide

Following a procedure analogous to the procedure described in Example 1usingN-{3-[5-(2-chloro-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide(150 mg, 0.264 mmol) and 3-(methylthio)-1-propanamine (300 mg, 2.85mmol), the title compound was obtained as a crude yellow foam and useddirectly in the next step. MS (ESI): 637.2 [M+H]⁺.

Step B:2,6-Difluoro-N-{2-fluoro-3-[5-(2-{[3-(methylsulfonyl)propyl]amino}-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]phenyl}benzenesulfonamide

Following a procedure analogous to the procedure described in Example12, Step B using crude2,6-difluoro-N-{2-fluoro-3-[5-(2-{[3-(methylthio)propyl]amino}-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]phenyl}benzenesulfonamideand oxone (527 mg, 0.857 mmol) the title compound was obtained as awhite solid (83 mg, 46% yield over 2 steps). ¹H NMR (400 MHz, DMSO-d6) δppm 10.87 (s, 1H), 7.88 (d, J=5.4 Hz, 1H), 7.59-7.76 (m, 1H), 7.42 (td,J=7.3, 2.3 Hz, 1H), 7.16-7.33 (m, 5H), 5.67 (br. s., 1H), 3.63-3.77 (m,4H), 3.39-3.51 (m, 4H), 3.22-3.31 (m, 2H), 3.08-3.19 (m, 2H), 2.96 (s,3H), 1.82-2.00 (m, 2H). MS (ESI): 669.2 [M+H]⁺.

Example 16N-(5-{2-(1,1-Dimethylethyl)-5-[2-({trans-4[(methylsulfonyl)amino]cyclohexyl}amino)-4-pyrimidinyl]-1,3-thiazol-4-yl}-2-fluorophenyl)-2,6-difluorobenzenesulfonamide

Step A: 1,1-Dimethylethyl {4-[(methylsulfonyl)amino]cyclohexyl}carbamate

The trans-N-boc-1,4-cyclohexanediamine (1.00 g, 4.67 mmol) was dissolvedin DCM (50 mL). Next, TEA was added (1.301 mL, 9.33 mmol), followed bymethanesulfonyl chloride (0.397 mL, 5.13 mmol). The reaction was allowedto stir at rt for 22 h. The reaction mixture was partitioned between DCM(100 mL) and water (25 mL). The phases were separated and the aqueousphase was extracted with DCM (50 mL). Combined organic layer was driedover MgSO₄ for 20 h overnight. Filtered and evaporated to dryness togive the title compound of Step A as a solid (0.924 g). ¹H NMR (400 MHz,DMSO-d₆) δ ppm 3.32 (s, 8H), 2.89 (s, 3H), 1.83-1.91 (m, 1H), 1.70-1.78(m, 1H), 1.37 (s, 9H).

Step B: N-(4-Aminocyclohexyl)methanesulfonamide

1,1-Dimethylethyl {4-[(methylsulfonyl)amino]cyclohexyl}carbamate (0.922g, 3.15 mmol) was dissolved in DCM (50 mL). TFA was added (2.429 mL,31.5 mmol) and the reaction allowed to stir at rt for 1 h. Evaporatedoff the volatiles and added DCM (50 mL) followed by evaporation ofvolatiles. The DCM addition/evaporation was repeated several times togive a maroon semi-solid. The residual semi-solid was treated withdiethyl ether (10 mL) after which the suspension was sonicated andtriturated, then filtered. Solids were triturated with more diethylether (10 mL). The product was suction dried to give title compound ofStep B as a light pink solid (0.938 g). ¹H NMR (400 MHz, DMSO-d₆) δ ppm7.80 (br. s., 2H), 7.07 (d, J=7.2 Hz, 1H), 3.33 (s, 2H), 3.01-3.14 (m,1H), 2.78-3.01 (m, 2H), 1.80-2.02 (m, 4H), 1.17-1.47 (m, 4H).

Step C:N-(5-{2-(1,1-Dimethylethyl)-5-[2-({trans-4-[(methylsulfonyl)amino]cyclohexyl}amino)-4-pyrimidinyl]-1,3-thiazol-4-yl}-2-fluorophenyl)-2,6-difluorobenzenesulfonamide

N-{5-[5-(2-Chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide(50 mg, 0.093 mmol) and N-(4-aminocyclohexyl)-methanesulfonamide (19.62mg, 0.102 mmol) were dissolved in n-butanol (1 mL) and TEA (0.052 mL,0.371 mmol) was added. The reaction was stirred in a closed vessel at90° C. for 18 h. The reaction mixture was cooled to rt and solvent wasremoved. The residue was purified via Gilson Acidic HPLC (10 to 90%gradient, Acetonitrile/H2O+TFA; C18 column). Desired fractions werecombined and solvent removed to give the title compound as a white solid(0.006 g). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.95 (s, 1H), 8.09 (d, J=5.0Hz, 1H), 7.67-7.78 (m, 1H), 7.41 (d, J=3.5 Hz, 1H), 7.28 (q, J=8.7 Hz,2H), 7.00 (dt, J=2.6, 1.3 Hz, 1H), 6.10-6.28 (m, 1H), 3.56-3.70 (m, 1H),3.41-3.52 (m, 1H), 3.09 (td, J=4.2, 1.7 Hz, 1H), 2.92 (s, 3H), 1.83-1.98(m, 4H), 1.21-1.50 (m, 13H). MS (ESI): 695 [M+H]⁺.

Example 172,6-Difluoro-N-{3-[5-[2-({trans-4-[(methylsulfonyl)amino]cyclohexyl}amino)-4-pyrimidinyl]-2-(1-pyrrolidinyl)-1,3-thiazol-4-yl]phenyl}benzenesulfonamide

N-{3-[5-(2-Chloro-4-pyrimidinyl)-2-(1-pyrrolidinyl)-1,3-thiazol-4-yl]phenyl}-2,6-difluorobenzenesulfonamidewas dissolved in n-butanol and N-(4-aminocyclohexyl)methanesulfonamide(27.0 mg, 0.140 mmol) was added at rt followed by TEA (52.2 μl, 0.375mmol). The reaction was heated to 60° C. for 12 h. Purified via GilsonAcidic HPLC (10 to 90% gradient, Acetonitrile/H2O+TFA; C18 column).Desired fractions were combined and washed with NaHCO₃, dried over MgSO₄and solvent removed to give the title compound as a yellow solid (0.010g). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.73 (d, J=5.1 Hz, 1H), 7.38-7.55(m, 1H), 7.11-7.31 (m, 2H), 6.93-7.10 (m, 3H), 6.72-6.88 (m, 1H),6.42-6.48 (m, 1H), 6.28-6.35 (m, 1H), 5.79-5.88 (m, 1H), 3.52-3.63 (m,1H), 3.29-3.45 (m, 6H), 3.05-3.16 (m, 1H), 2.91 (s, 3H), 1.77-2.02 (m,6H), 1.19-1.42 (m, 4H). MS (ESI): 690 [M+H]⁺.

Example 18N-{2-Chloro-3-[5-{2-[(2-methylpropyl)amino]-4-pyrimidinyl}-2-(tetrahydro-2H-pyran-4-yl)-1,3-thiazol-4-yl]phenyl}-2,6-difluorobenzenesulfonamide

Step A:N-{2-Chloro-3-[5-(2-chloro-4-pyrimidinyl)-2-(tetrahydro-2H-pyran-4-yl)-1,3-thiazol-4-yl]phenyl}-2,6-difluorobenzenesulfonamide

Recrystallized NBS (1.56 g, 8.8 mmol) was added to a suspension ofN-{2-chloro-3-[(E)-2-(2-chloro-4-pyrimidinyl)-1-hydroxyethenyl]phenyl}-2,6-difluorobenzenesulfonamide(4.02 g, 8.80 mmol) in DMA (15 mL) in an ice-bath. The reaction wasimmediately removed from the ice bath and allowed to warm to rt over 0.5h. Tetrahydro-2H-pyran-4-carbothioamide (1.27 g, 8.80 mmol) was addedand the reaction warmed in an oil bath (rt to 65° C.). The reaction wasdiluted with water (100 mL) which caused the precipitation of a yellowsolid. The solid was then dissolved by the addition of EtOAc (100 mL)and the phases separated. The aqueous phase was extracted with EtOAc (50mL). The combined organic phase was filtered through Whatman 1 PS (phaseseparating) paper and concentrated under vacuum to a crude orangeresidue. The residue was purified by silica gel chromatography elutingwith 0-100% EtOAc/hexanes to give the title compound of Step A as abright yellow solid (2.56 g; 50.1% yield). ¹H NMR (400 MHz, DMSO-d6) δppm 10.88 (s, 1H), 8.55 (d, J=5.4 Hz, 1H), 7.62-7.74 (m, 1H), 7.48-7.57(m, 2H), 7.42-7.47 (m, 1H), 7.22 (t, J=9.1 Hz, 2H), 6.54 (d, J=5.3 Hz,1H), 3.92 (d, J=11.0 Hz, 2H), 3.41-3.51 (m, 2H), 2.03 (br. s., 2H),1.69-1.83 (m, J=12.1, 12.1, 11.9, 4.2 Hz, 2H).

Step B:2,6-Difluoro-N-{2-fluoro-3-[5-{2-[(2-methylpropyl)amino]-4-pyrimidinyl}-2-(tetrahydro-2H-pyran-4-yl)-1,3-thiazol-4-yl]phenyl}benzenesulfonamide

N-{2-chloro-3-[5-(2-chloro-4-pyrimidinyl)-2-(tetrahydro-2H-pyran-4-yl)-1,3-thiazol-4-yl]phenyl}-2,6-difluorobenzenesulfonamide(0.15 g, 0.26 mmol) and isobutylamine (0.15 g, 2.01 mmol) were combinedin i-PrOH (3 mL) in a sealed vessel and heated at 80° C. for 16 h. Thereaction was concentrated to a yellow solid that was dissolved in DCMand delivered on the top of a pre-pack (5 g) SiO₂ cartridge. The residuewas purified by silica gel chromatography eluting with 0-100%DCM:MeOH:NH₄OH/84:15:1 in DCM. The resulting crude yellow product wasdissolved with DCM (10 mL) and the addition of hexanes precipitated thetitle compound as a yellow solid, which was collected and air-dried(0.100 g, 58.4% yield). ¹H NMR (400 MHz, DMSO-d6) δ ppm 10.82 (s, 1H),8.01 (d, J=5.1 Hz, 1H), 7.62-7.73 (m, 1H), 7.50 (s, 1H), 7.45 (t, J=7.8Hz, 1H), 7.35 (d, J=6.6 Hz, 2H), 7.21 (t, J=9.0 Hz, 2H), 5.66 (br. s.,1H), 3.91 (ddd, J=9.6, 2.0, 1.8 Hz, 2H), 3.41-3.50 (m, 2H), 3.22-3.31(m, 1H), 2.97-3.09 (m, 2H), 1.98 (dd, J=12.8, 1.9 Hz, 2H), 1.84 (dt,J=13.5, 6.8 Hz, 1H), 1.65-1.78 (m, 2H), 0.87 (d, J=6.7 Hz, 6H). MS (ESI)620.2 [M+H]⁺.

Example 19N-[2-Chloro-3-(2-(1,1-dimethylethyl)-5-{2-[(2-methylpropyl)amino]-4-pyrimidinyl}-1,3-thiazol-4-yl)phenyl]-2,6-difluorobenzenesulfonamide

Step A:N-{2-Chloro-3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]phenyl}-2,6-difluorobenzenesulfonamide

Following a procedure analogous to the procedure described in Example18, Step A usingN-{2-chloro-3-[(E)-2-(2-chloro-4-pyrimidinyl)-1-hydroxyethenyl]phenyl}-2,6-difluorobenzenesulfonamide(4.03 g, 8.80 mmol) and 2,2-dimethylpropanethioamide (1.03 g, 8.80mmol), the title compound was obtained as a bright yellow solid (2.25 g;43.7% yield). ¹H NMR (400 MHz, DMSO-d6) δ ppm 10.87 (s, 1H), 8.54 (d,J=5.3 Hz, 1H), 7.63-7.73 (m, 1H), 7.42-7.57 (m, 3H), 7.22 (t, J=9.2 Hz,2H), 6.53 (d, J=5.3 Hz, 1H), 1.42 (s, 9H).

Step B:N-[2-Chloro-3-(2-(1,1-dimethylethyl)-5-{2-[(2-methylpropyl)amino]-4-pyrimidinyl}-1,3-thiazol-4-yl)phenyl]-2,6-difluorobenzenesulfonamide

Following a procedure analogous to the procedure described in Example18, Step B usingN-{2-chloro-3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]phenyl}-2,6-difluorobenzenesulfonamide(0.15 g, 0.28 mmol) and isobutylamine (0.15 g, 2.01 mmol), the titlecompound was obtained as a yellow solid (0.078 g, 45.4% yield). ¹H NMR(400 MHz, DMSO-d6) δ ppm 10.81 (s, 1H), 8.01 (d, J=5.1 Hz, 1H),7.62-7.71 (m, 1H), 7.49-7.53 (m, 1H), 7.45 (t, J=7.7 Hz, 1H), 7.29-7.39(m, 2H), 7.21 (t, J=9.1 Hz, 2H), 5.65 (d, 1H), 3.03 (br. s., 2H), 1.84(dt, J=13.4, 6.7 Hz, 1H), 1.40 (s, 9H), 0.88 (d, J=6.6 Hz, 6H). MS (ESI)592.2 [M+H]⁺.

Example 20N-{2-Chloro-3-[5-{2-[(2-methylpropyl)amino]-4-pyrimidinyl}-2-(4-morpholinyl)-1,3-thiazol-4-yl]phenyl}-2,6-difluorobenzenesulfonamide

Step A:N-{2-Chloro-3-[5-(2-chloro-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]phenyl}-2,6-difluorobenzenesulfonamide

Following a procedure analogous to the procedure described in Example18, Step A usingN-{2-chloro-3-[(E)-2-(2-chloro-4-pyrimidinyl)-1-hydroxyethenyl]phenyl}-2,6-difluorobenzenesulfonamide(4.05 g, 8.83 mmol) and 4-morpholinecarbothioamide (1.29 g, 8.83 mmol),the title compound was obtained as a bright yellow solid (2.61 g; 48%yield). ¹H NMR (400 MHz, DMSO-d6) δ ppm 10.87 (s, 1H), 8.29 (d, J=5.5Hz, 1H), 7.64-7.74 (m, 1H), 7.46-7.56 (m, 2H), 7.39 (dd, J=7.1, 1.7 Hz,1H), 7.23 (t, J=9.1 Hz, 2H), 6.19 (d, J=5.5 Hz, 1H), 3.71 (t, J=4.6 Hz,4H), 3.54 (t, J=4.3 Hz, 4H).

Step B:N-{2-Chloro-3-[5-{2-[(2-methylpropyl)amino]-4-pyrimidinyl}-2-(4-morpholinyl)-1,3-thiazol-4-yl]phenyl}-2,6-difluorobenzenesulfonamide

Following a procedure analogous to the procedure described in Example18, Step B usingN-{2-Chloro-3-[5-(2-chloro-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]phenyl}-2,6-difluorobenzenesulfonamide(0.16 g, 0.27 mmol) and isobutylamine (0.15 g, 2.01 mmol), the titlecompound was obtained as a pale yellow solid (0.026 g; 14.1% yield). ¹HNMR (400 MHz, DMSO-d6) δ ppm 10.79 (s, 1H), 7.84 (d, J=5.3 Hz, 1H),7.60-7.72 (m, 1H), 7.46-7.51 (m, 1H), 7.43 (t, J=7.6 Hz, 1H), 7.30 (d,J=6.9 Hz, 1H), 7.21 (t, J=9.1 Hz, 2H), 7.12 (d, J=0.5 Hz, 1H), 5.42 (d,J=4.9 Hz, 1H), 3.70 (t, J=4.6 Hz, 4H), 3.44 (t, J=4.6 Hz, 4H), 3.02 (t,J=6.2 Hz, 2H), 0.87 (d, J=6.7 Hz, 9H). MS (ESI) 621.2 [M+H]⁺.

Example 21N-{3-[5-(2-Amino-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]-2-chlorophenyl}-2,6-difluorobenzenesulfonamide

In a pressure vessel was placedN-{2-Chloro-3-[5-(2-chloro-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]phenyl}-2,6-difluorobenzenesulfonamide(300 mg, 0.513 mmol) and NH₄OH (2 mL) and 1,4-dioxane (2 mL) were added.The vessel was sealed and heated at 100° C. for 18 h. The reactionmixture was cooled, concentrated onto silica and the residue was columnchromatographed to give the title compound (0.10 g, 35% yield). ¹H NMR(400 MHz, DMSO-d₆) δ ppm 10.81 (br. s., 1H), 7.81 (d, J=5.3 Hz, 1H),7.62-7.73 (m, 1H), 7.39-7.52 (m, 2H), 7.28-7.34 (m, 1H), 7.21 (t, J=9.1Hz, 2H), 6.55 (s, 2H), 5.44 (d, J=5.3 Hz, 1H), 3.70 (t, J=4.7 Hz, 4H),3.44 (t, J=4.6 Hz, 4H). MS (ES+): 566 [M+H]⁺.

Example 22N-{2-Chloro-3-[5-{2-[(2-methylpropyl)amino]-4-pyrimidinyl}-2-(4-morpholinyl)-1,3-thiazol-4-yl]phenyl}-2,5-difluorobenzenesulfonamide

Step A:N-{2-Chloro-3-[5-(2-chloro-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]phenyl}-2,5-difluorobenzenesulfonamide

Following a procedure analogous to the procedure described in Example18, Step A using NBS (0.41 g, 2.29 mmol),N-{2-chloro-3-[(E)-2-(2-chloro-4-pyrimidinyl)-1-hydroxyethenyl]phenyl}-2,5-difluorobenzenesulfonamide(1.0 g, 2.18 mmol) and 4-morpholinecarbothioamide (0.35 g, 2.40 mmol)the title compound was obtained as a yellow solid (1.27 g; 95% yield).¹H NMR (400 MHz, DMSO-d6) δ ppm 10.74 (s, 1H), 8.31 (d, J=5.5 Hz, 1H),7.28-7.75 (m, 8H), 6.20 (d, J=5.5 Hz, 1H), 3.71 (t, J=4.7 Hz, 4H), 3.54(t, J=4.6 Hz, 4H).

Step B:N-{2-Chloro-3-[5-{2-[(2-methylpropyl)amino]-4-pyrimidinyl}-2-(4-morpholinyl)-1,3-thiazol-4-yl]phenyl}-2,5-difluorobenzenesulfonamide

Following a procedure analogous to the procedure described in Example18, Step B usingN-{2-chloro-3-[5-(2-chloro-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]phenyl}-2,5-difluorobenzenesulfonamide(0.15 g, 0.26 mmol) and isobutylamine (0.19 g, 2.57 mmol) the titlecompound was obtained as a yellow solid (0.132 g, 79% yield). ¹H NMR(400 MHz, DMSO-d6) δ ppm 10.70 (br. s., 1H), 7.84 (d, J=4.9 Hz, 1H),7.38-7.62 (m, 6H), 7.29 (d, J=7.1 Hz, 1H), 5.42 (d, J=4.9 Hz, 1H), 3.70(br. s., 4H), 3.44 (br. s., 4H), 3.02 (d, J=5.8 Hz, 2H), 1.83 (ddd,J=12.8, 6.7, 6.5 Hz, 1H), 0.87 (d, J=6.5 Hz, 6H). m/z (ESI) 621.2[M+H]⁺.

Example 23N-[2-Chloro-3-(2-(1,1-dimethylethyl)-5-{2-[(2-methylpropyl)amino]-4-pyrimidinyl}-1,3-thiazol-4-yl)phenyl]-2,5-difluorobenzenesulfonamide

Step A:N-{2-Chloro-3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]phenyl}-2,5-difluorobenzenesulfonamide

To a solution ofN-{2-chloro-3-[(E)-2-(2-chloro-4-pyrimidinyl)-1-hydroxyethenyl]phenyl}-2,5-difluorobenzenesulfonamide(3.0 g, 6.55 mmol) in DMA (25 mL) was added NBS (1.165 g, 6.55 mmol).After stirring for 1 h at rt, 2,2-dimethylpropanethioamide (0.767 g,6.55 mmol) was added and the reaction mixture was stirred at 80° C. for2 h. The reaction mixture was diluted with EtOAc (100 mL) and extractedfive times with water. The organic layer was dried over anhydrous NaSO₄,adsorbed onto silica gel, and purified via column chromatography,eluting with 0-50% EtOAc/DCM. The desired fractions were combined andconcentrated to generate 1.31 g (2.36 mmol, 36.0% yield) of the titlecompound as a yellow powder. ¹H NMR (400 MHz, DMSO-d₆): δ 10.74 (s, 1H),8.56 (d, J=5.4 Hz, 1H), 7.41-7.58 (m, 6H), 6.57 (d, J=5.4 Hz, 1H), 1.42(s, 9H). MS (ESI): 555.0 [M+H]+.

Step B:N-[2-Chloro-3-(2-(1,1-dimethylethyl)-5-{2-[(2-methylpropyl)amino]-4-pyrimidinyl}-1,3-thiazol-4-yl)phenyl]-2,5-difluorobenzenesulfonamide

Following a procedure analogous to the procedure described in Example18, Step B usingN-{2-chloro-3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]phenyl}-2,5-difluorobenzenesulfonamide(0.10 g; 0.18 mmol) and isobutylamine (0.13 g; 1.81 mmol) the titlecompound was obtained as a yellow solid (0.050 g, 44.6% yield). ¹H NMR(400 MHz, DMSO-d6) δ ppm 10.70 (br. s., 1H), 8.00 (d, J=5.1 Hz, 1H),7.40-7.60 (m, 5H), 7.28-7.37 (m, 2H), 5.65 (d, 1H), 3.01 (br. s., 2H),1.76-1.89 (m, J=13.3, 6.7, 6.7, 6.7, 6.7 Hz, 1H), 1.39 (s, 9H), 0.87 (d,J=6.7 Hz, 6H). MS (ESI) 592.2 [M+H]⁺.

Example 24N-{3-[5-(2-Amino-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]-2-chlorophenyl}-2-furansulfonamide

Step A: Methyl 2-chloro-3-{[(2-propen-1-yloxy)carbonyl]amino}benzoate

To a solution of methyl 3-amino-2-chlorobenzoate (29 g, 0.162 mol) inTHF (50 mL) and saturated NaHCO₃ (200 mL) was added 2-propen-1-ylchloridocarbonate (24 g, 0.194 mol) dropwise at 0° C. The reactionmixture was allowed to warm to rt for 2 h. The reaction was extractedwith EtOAc (2×200 mL). The organic layer was dried over Na₂SO₄, and thesolvent was removed to give the crude product of Step A, which wasdirectly used to the next step. (42 g, 96.3% yield). ¹H NMR (400 MHz,CDCl₃) δ ppm 8.30-8.37 (m, 1H), 7.47-7.51 (m, 1H), 7.35-7.43 (br, 1H),7.28-7.33 (m, 1H), 5.90-6.06 (m, 1H), 5.25-5.41 (m, 2H), 4.68-4.70 (m,2H), 3.91 (s, 3H).

Step B: 2-Propen-1-yl{2-chloro-3-[(E)-2-(2-chloro-4-pyrimidinyl)-1-hydroxyethenyl]phenyl}carbamate

Following a procedure analogous to the procedure described inIntermediate 5, Step B using methyl2-chloro-3-{[(2-propen-1-yloxy)carbonyl]amino}benzoate (30 g, 0.11 mol)and 2-chloro-4-methylpyrimidine (15.8 g, 0.12 mol) the title compound ofStep B was prepared (29 g, 79.6% yield). ¹H NMR (400 MHz, CDCl₃) δ ppm13.52-13.58 (br, 0.9H), 8.41-8.42 (m, 1H), 8.22-8.27 (m, 1H), 7.28-7.35(m, 2.2H), 7.21-7.24 (m, 1.2H), 6.85-6.88 (m, 1H), 5.91-6.02 (m, 1H),5.73 (s, 1H), 5.23-5.40 (m, 2H), 4.66-4.70 (m, 2H).

Step C: 2-Propen-1-yl{2-chloro-3-[5-(2-chloro-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]phenyl}carbamate

Following a procedure analogous to the procedure described in Example18, Step A using 2-propen-1-yl{2-chloro-3-[(2-chloro-4-pyrimidinyl)acetyl]phenyl}carbamate (3.00 g,8.19 mmol), NBS (1.531 g, 8.60 mmol) and 4-morpholinecarbothioamide(1.677 g, 11.47 mmol) the title compound of Step C was obtained as anorange solid (4.03 g, 7.86 mmol, 96% yield). ¹H NMR (400 MHz, DMSO-d₆) δppm 9.29 (s, 1H), 8.33 (d, J=5.5 Hz, 1H), 7.67-7.84 (m, 1H), 7.48 (t,J=7.8 Hz, 1H), 7.29 (dd, J=7.7, 1.5 Hz, 1H), 6.41 (d, J=5.5 Hz, 1H),5.83-6.08 (m, 1H), 5.36 (dd, J=17.2, 1.5 Hz, 1H), 5.23 (dd, J=10.4, 1.5Hz, 1H), 4.62 (d, J=5.3 Hz, 2H), 3.73 (t, J=4.8 Hz, 4H), 3.57 (t, J=4.8Hz, 4H). MS (ESI): 491.98 [M+H]⁺.

Step D:{2-Chloro-3-[5-(2-chloro-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]phenyl}amine

Following a procedure analogous to the procedure described inIntermediate 13 using 2-propen-1-yl{2-chloro-3-[5-(2-chloro-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]phenyl}carbamate(2.50 g, 5.08 mmol) the title compound of Step D was obtained as ayellow solid (2.08 g, 4.99 mmol, 98% yield). MS (ESI): 407.97 [M+H]⁺.

Step E:N-{2-Chloro-3-[5-(2-chloro-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]phenyl}-2-furansulfonamide

Following a procedure analogous to the procedure described inIntermediate 14 using{2-chloro-3-[5-(2-chloro-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]phenyl}amine(1.03 g, 2.52 mmol) and 2-furansulfonyl chloride (0.588 g, 3.53 mmol)the title compound of Step E was obtained as an off-white solid (430 mg,0.735 mmol, 29.1% yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.53 (s, 1H),8.38 (d, J=5.5 Hz, 1H), 7.91 (d, J=0.9 Hz, 1H), 7.43-7.58 (m, 2H),7.31-7.43 (m, 1H), 7.08 (d, J=3.5 Hz, 1H), 6.55 (dd, J=3.5, 1.8 Hz, 1H),6.18 (d, J=5.5 Hz, 1H), 3.71 (t, J=4.8 Hz, 4H), 3.55 (t, J=4.7 Hz, 4H).MS (ESI): 537.96 [M+H]⁺.

Step F:N-{3-[5-(2-Amino-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]-2-chlorophenyl}-2-furansulfonamide

Following a procedure analogous to the procedure described in Example 21usingN-{2-chloro-3-[5-(2-chloro-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]phenyl}-2-furansulfonamide(0.100 g, 0.186 mmol) and ammonium hydroxide (1.21 mL, 9.29 mmol) heatedto 120° C. for 20 min in a microwave reactor the title compound wasobtained as a white solid (54 mg, 0.104 mmol, 56.0% yield). ¹H NMR (400MHz, DMSO-d₆) δ ppm 10.47 (s, 1H), 7.90 (d, J=5.5 Hz, 2H), 7.43 (d,J=3.8 Hz, 2H), 7.30 (d, J=3.3 Hz, 1H), 7.03 (d, J=3.3 Hz, 1H), 6.43-6.62(m, 3H), 5.47 (d, J=5.3 Hz, 1H), 3.71 (t, J=4.7 Hz, 4H), 3.45 (t, J=4.7Hz, 4H). MS (ESI): 519.00 [M+H]⁺.

Example 25N-{2-Chloro-3-[5-(2-methyl-4-pyrimidinyl)-2-(tetrahydro-2H-pyran-4-yl)-1,3-thiazol-4-yl]phenyl}-2,6-difluorobenzenesulfonamidetrifluoroacetate

A solution ofN-{2-chloro-3-[5-(2-chloro-4-pyrimidinyl)-2-(tetrahydro-2H-pyran-4-yl)-1,3-thiazol-4-yl]phenyl}-2,6-difluorobenzenesulfonamide(0.16 g; 0.27 mmol) in 1,4-dioxane (4 mL) with PdCl₂(dppf) (0.055 g,0.075 mmol) was degassed for 5 min. To this mixture was added 2.0Mdimethylzinc in toluene (0.4 mL, 0.80 mmol). The reaction mixture washeated to 80° C. After 2 h, the reaction was quenched slowly with MeOH(25 mL). The reaction was further diluted with DCM (50 mL), filteredthrough a nylon membrane and evaporated to a crude yellow residue.Purification was accomplished with a C-18 reverse phase column running agradient of 10-90% MeCN/H₂O (+0.1% TFA) over 14 min to afford the titlecompound as an ivory solid (0.051 g; 27.1% yield). ¹H NMR (400 MHz,DMSO-d6) δ ppm 10.84 (s, 1H), 8.45 (d, J=5.4 Hz, 1H), 7.61-7.73 (m, 1H),7.51-7.55 (m, 1H), 7.48 (t, J=7.7 Hz, 1H), 7.41 (dd, J=7.3, 1.9 Hz, 1H),7.21 (t, J=9.1 Hz, 2H), 6.35 (d, J=5.4 Hz, 1H), 3.92 (ddd, J=9.6, 2.0,1.8 Hz, 2H), 3.46 (td, J=11.5, 1.9 Hz, 2H), 3.25-3.35 (m, 1H), 2.58 (s,3H), 2.01 (dd, J=12.7, 2.0 Hz, 2H), 1.68-1.81 (m, 2H). MS (ESI) 563.1[M+H]⁺.

Example 26N-{2-Chloro-3-[5-(4-pyrimidinyl)-2-(tetrahydro-2H-pyran-4-yl)-1,3-thiazol-4-yl]phenyl}-2,6-difluorobenzenesulfonamide

To a solution ofN-{2-chloro-3-[5-(2-chloro-4-pyrimidinyl)-2-(tetrahydro-2H-pyran-4-yl)-1,3-thiazol-4-yl]phenyl}-2,6-difluorobenzenesulfonamide(0.15 g, 0.26 mmol) and ammonium formate (0.17 g, 2.6 mmol) in EtOAc (7mL) and MeOH (7 mL) was added 20% palladium hydroxide on carbon (0.17 g,0.24 mmol). The reaction mixture was heated to 60° C. for 2 h. Thepalladium was filtered off using a nylon membrane. The filtrate wasconcentrated under vacuum to a crude yellow solid. The residue waspurified by silica gel chromatography eluting 0-100% EtOAC/hexanes. Theresulting solid was dissolved in DCM (5 mL) and hexanes added to affordthe title compound as a pale yellow solid (58 mg, 38.3% yield). ¹H NMR(400 MHz, DMSO-d6) δ ppm 10.85 (s, 1H), 9.11 (d, J=1.3 Hz, 1H), 8.57 (d,J=5.4 Hz, 1H), 7.60-7.73 (m, 1H), 7.52-7.55 (m, 1H), 7.49 (t, J=7.7 Hz,1H), 7.41-7.45 (m, 1H), 7.20 (t, J=9.1 Hz, 2H), 6.56 (dd, J=5.4, 1.3 Hz,1H), 3.92 (ddd, J=9.6, 2.0, 1.9 Hz, 2H), 3.46 (td, J=11.6, 1.9 Hz, 2H),2.00 (dd, J=12.8, 1.9 Hz, 2H), 1.68-1.80 (m, 2H), *Note: The methine(—H) peak of the THP(tetrahydro-2H-pyran-4-yl) group is submerged underthe water peak at 3.33 ppm causing broadening. MS (ESI) 549.1 [M+H]⁺.

Example 27N-{2-Chloro-3-[2-(4-morpholinyl)-5-(4-pyrimidinyl)-1,3-thiazol-4-yl]phenyl}-2,6-difluorobenzenesulfonamide

To a solution ofN-{2-chloro-3-[5-(2-chloro-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]phenyl}-2,6-difluorobenzenesulfonamide(0.15 g, 0.26 mmol) and ammonium formate (0.16 g, 2.6 mmol) in EtOAc (7mL) and MeOH (7 mL) was added 20% palladium hydroxide on carbon (0.16 g,0.23 mmol). The reaction mixture was heated to 60° C. for 2 h. Thepalladium was filtered off using a nylon membrane. The filtrate wasconcentrated under vacuum to a crude yellow solid. The residue waspurified by silica gel chromatography eluting 10-100% EtOAc/hexanes toafford the title compound as a bright yellow solid (0.045 g; 29.7%yield). ¹H NMR (400 MHz, DMSO-d6) δ ppm 10.85 (s, 1H), 8.96 (d, J=1.3Hz, 1H), 8.36 (d, J=5.6 Hz, 1H), 7.62-7.75 (m, 1H), 7.44-7.55 (m, 2H),7.38 (d, J=6.1 Hz, 1H), 7.22 (t, J=9.1 Hz, 2H), 6.25 (dd, J=5.6, 1.3 Hz,1H), 3.66-3.76 (m, 4H), 3.46-3.54 (m, 4H). MS (ESI) 550.1 [M+H]⁺.

Example 28N-{2-Chloro-3-[5-(2-methyl-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]phenyl}-2,5-difluorobenzenesulfonamide

A solution ofN-{2-chloro-3-[5-(2-chloro-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]phenyl}-2,5-difluorobenzenesulfonamide(0.15 g, 0.26 mmol) in 1,4-dioxane (3 mL) with PdCl₂(dppf) (0.047 g,0.064 mmol) was degassed for 5 min. To this mixture was added 2.0Mdimethylzinc in toluene (0.39 mL, 0.77 mmol). The reaction mixture washeated to 80° C. After 2 h, the reaction was quenched slowly with MeOH(15 mL) and then was further diluted with DCM (50 mL), filtered througha nylon membrane and evaporated to a crude yellow residue. The residuewas purified by silica gel chromatography eluting 0-100% EtOAC/hexanes,followed by 10% EtOH/EtOAc. The resulting solid was dissolved in DCM (10mL) and hexanes (20 mL) added to afford the title compound as a yellowsolid (0.02 g; 13.1% yield). ¹H NMR (400 MHz, DMSO-d6) δ ppm 10.72 (s,1H), 8.26 (d, J=5.6 Hz, 1H), 7.51-7.60 (m, 2H), 7.40-7.50 (m, 3H),7.32-7.39 (m, 1H), 6.07 (d, J=5.5 Hz, 1H), 3.71 (t, J=4.8 Hz, 4H),3.48-3.53 (m, 4H) *Note: The 2-Me group is submerged under the waterpeak at 2.5 ppm. MS (ESI) 564.1 [M+H]⁺.

Example 292,4-Difluoro-N-{2-fluoro-5-[2-(1-methylethyl)-5-(2-{[2-(methylsulfonyl)ethyl]amino}-4-pyrimidinyl)-1,3-thiazol-4-yl]phenyl}benzenesulfonamide

Step A:N-{5-[5-(2-Chloro-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,4-difluorobenzenesulfonamide

To a solution of5-[5-(2-chloro-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]-2-fluoroaniline(12 g, 34.4 mmol) in DCM (100 mL) was added pyridine (8.2 g, 103 mmol).The mixture was cooled to 0° C. 2,4-Difluorobenzene-1-sulfonyl chloride(7.32 g, 34.4 mmol) in DCM (30 mL) was added dropwise to the mixture.The reaction was stirred at rt for 4 h. Then the reaction was washedwith water (200 mL), and extracted with DCM (2×200 mL). The organiclayer was washed with brine, dried over anhydrous NaSO₄, filtrated andconcentrated under reduced pressure to give the crude product, which waspurified by column chromatography on silica gel (petroleum ether:DCM1:1) to afford the title compound (9.0 g, 49.8% yield). ¹H NMR (400 MHz,DMSO-d6) δ ppm 10.63-10.70 (br, 1H), 8.55 (d, J=5.3 Hz, 1H), 7.71-7.82(m, 1H), 7.50-7.57 (m, 1H), 7.41-7.48 (m, 1H), 7.34-7.40 (m, 1H),7.24-7.32 m, 1H), 7.15-7.23 (m, 1H), 7.08 (d, J=5.3, 1H), 3.27-3.37 (m,1H), 1.36 (d, J=6.8 Hz, 6H). MS (ES+): 525 [M+H]⁺.

Step B:2,4-Difluoro-N-{2-fluoro-5-[2-(1-methylethyl)-5-(2-{[2-(methylsulfonyl)ethyl]amino}-4-pyrimidinyl)-1,3-thiazol-4-yl]phenyl}benzenesulfonamide

[2-(Methylsulfonyl)ethyl]amine (352 mg, 2.86 mmol) andN-{5-[5-(2-chloro-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,4-difluorobenzenesulfonamide(150 mg, 0.286 mmol) were combined and heated to 55° C. overnight.Isopropanol (1 mL) was added to the reaction mixture and stirred anadditional 30 min. The reaction mixture was cooled to rt and partitionedbetween DCM and 10% aqueous HCl. The organic layer was separated anddried over MgSO₄, filtered, and concentrated over silica gel. The crudeproduct was chromatographed on silica gel eluting with 100% DCM to 6:4[DCM:(9:1 EtOAc:MeOH)]. The clean fractions were combined andconcentrated to obtain the title compound as a white foam (82.1 mg; 45%yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.65 (s, 1H) 8.14 (d, J=4.2 Hz,1H) 7.72 (q, J=7.6 Hz, 1H) 7.54 (t, J=9.7 Hz, 1H) 7.47 (br. s., 1H)7.30-7.42 (m, 2H) 7.11-7.30 (m, 2H) 6.23 (d, J=1.2 Hz, 1H) 3.64 (d,J=0.9 Hz, 2H) 3.20-3.40 (m, 2H range includes water peak) 2.99 (s, 3H)1.33 (d, J=6.7 Hz, 6H). MS (ESI): 612.2 [M+H]⁺.

Example 30N-{3-[2-(1-Methylethyl)-5-(2-{[2-(methylsulfonyl)ethyl]amino}-4-pyrimidinyl)-1,3-thiazol-4-yl]phenyl}-2-furansulfonamide

Step A:N-{3-[5-(2-Chloro-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]phenyl}-2-furansulfonamide

Following a procedure analogous to the procedure described inIntermediate 14 using3-[5-(2-chloro-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]aniline(3 g, 9.1 mmol) and furan-2-sulfonyl chloride (1.81 g, 10.9 mmol) thetitle compound was obtained (2.0 g, 48.9% yield). ¹H NMR (400 MHz,DMSO-d6) δ ppm 10.74-10.87 (br, 1H), 8.53 (d, J=5.3 Hz, 1H), 7.91-7.93(m, 1H), 7.33-7.38 (m, 1H), 7.21-7.28 (m, 3H), 7.10-7.13 (m, 1H), 6.98(d, J=5.3 Hz, 1H), 6.57-6.60 (m, 1H), 3.23-3.35 (m, 1H), 1.36 (d, J=6.8Hz, 6H). MS (ES+): 661 [M+H]⁺.

Step B:N-{3-[2-(1-Methylethyl)-5-(2-{[2-(methylsulfonyl)ethyl]amino}-4-pyrimidinyl)-1,3-thiazol-4-yl]phenyl}-2-furansulfonamide

[2-(Methylsulfonyl)ethyl]amine (267 mg, 2.169 mmol) andN-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]phenyl}-2-furansulfonamide(100 mg, 0.217 mmol) were combined and heated to 56° C. overnight. Thereaction mixture was cooled to rt and diluted with DCM and 10% aqueousHCl. The layers were separated and the water layer was extracted twicemore with DCM. The combined organic layers were dried over MgSO₄,filtered and concentrated to yield an oil. The oil was chromatographedon silica gel eluting with 100% DCM to 4:6 [DCM:(9:1 EtOAc:MeOH)]. Theclean fractions were combined and concentrated to yield an oil. Diethylether was added to the oil and concentrated to obtain the title compoundas a light brown solid (25.1 mg, 20% yield). ¹H NMR (400 MHz, DMSO-d₆heated to 60° C.) δ ppm 10.53-10.65 (m, 1H) 8.06-8.16 (m, 1H) 7.88 (s,1H) 7.30-7.42 (m, 1H) 7.16-7.30 (m, 4H) 7.05 (d, J=3.6 Hz, 1H) 6.53-6.65(m, 1H) 6.14-6.27 (m, 1H) 3.59-3.74 (m, 2H) 3.24-3.43 (m, 3H) 2.97 (br.s., 3H) 1.36 (dd, J=6.6, 2.7 Hz, 6H). MS (ESI): 548.0[M+H]⁺.

Example 31N-{3-[2-(1-Methylethyl)-5-(2-{[2-(methylsulfonyl)ethyl]amino}-4-pyrimidinyl)-1,3-thiazol-4-yl]phenyl}-2-thiophenesulfonamide

Step A:N-{3-[5-(2-Chloro-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]phenyl}-2-thiophenesulfonamide

Following a procedure analogous to the procedure described inIntermediate 14, using3-[5-(2-chloro-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]aniline(600 mg, 1.8 mmol) and thiophene-2-sulfonyl chloride (331 mg, 1.1 mmol)the title compound was obtained (760 mg, 87.8% yield). ¹H NMR (400 MHz,CDCl₃) δ ppm 8.27 (d, J=5.3 Hz, 1H), 7.51-7.57 (m, 2H), 7.29-7.38 (m,2H), 7.20-7.27 (m, 2H), 7.13-7.17 (br, 1H), 6.98-7.03 (m, 1H), 6.88 (d,J=5.3 Hz, 1H), 3.27-3.37 (m, 1H), 1.43 (d, J=7.1 Hz, 6H). MS (ES+): 477[M+H]⁺.

Step B:N-{3-[2-(1-Methylethyl)-5-(2-{[2-(methylsulfonyl)ethyl]amino}-4-pyrimidinyl)-1,3-thiazol-4-yl]phenyl}-2-thiophenesulfonamide

Following a procedure analogous to the procedure described in Example 1using 2-aminoethyl-methyl-sulfone (258 mg, 2.096 mmol) andN-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]phenyl}-2-thiophenesulfonamide(100 mg, 0.210 mmol) the title compound was obtained as a light yellowsolid (20 mg, 17% yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.49 (s, 1H)8.07 (d, J=4.9 Hz, 1H) 7.82-7.92 (m, 1H) 7.46-7.52 (m, 1H) 7.37-7.46 (m,1H) 7.28-7.36 (m, 1H) 7.12-7.25 (m, 3H) 7.04-7.12 (m, 1H) 6.04-6.14 (m,1H) 3.55-3.69 (m, 2H) 3.30-3.37 (m, 3H) 2.97 (s, 3H) 1.32 (d, J=6.8 Hz,6H). MS (ESI): 564.1[M+H]⁺.

Example 322,6-Difluoro-N-{3-[5-(2-{[2-(methylsulfonyl)ethyl]amino}-4-pyrimidinyl)-2-(1-pyrrolidinyl)-1,3-thiazol-4-yl]phenyl}benzenesulfonamide

Following a procedure analogous to the procedure described in Example 1using 2-aminoethyl-methyl-sulfone (923 mg, 7.49 mmol) andN-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1-pyrrolidinyl)-1,3-thiazol-4-yl]phenyl}-2,6-difluorobenzenesulfonamide(400 mg, 0.749 mmol) the title compound was obtained as a white solid(27 mg, 4% yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.87-11.12 (m, 1H)7.75 (d, J=5.4 Hz, 1H) 7.55-7.72 (m, 1H) 7.24-7.38 (m, 1H) 7.10-7.25 (m,4H) 7.08 (d, J=7.8 Hz, 1H) 5.57-5.85 (m, 1H) 3.54-3.70 (m, 2H) 3.29-3.43(m, 7H) 2.88-3.05 (m, 4H) 1.86-2.04 (m, 3H). MS (ESI): 621.1 [M+H]⁺.

Example 33N-{3-[2-(1-Methylethyl)-5-(2-{[2-(methylsulfonyl)ethyl]amino}-4-pyrimidinyl)-1,3-thiazol-4-yl]phenyl}-3-pyridinesulfonamide

Step A:N-{3-[5-(2-Chloro-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]phenyl}-3-pyridinesulfonamide

Following a procedure analogous to the procedure described inIntermediate 14 using3-[5-(2-Chloro-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]aniline(3 g, 9.1 mmol) and pyridine-3-sulfonyl chloride (1.93 g, 10.9 mmol) thetitle compound was obtained (3.1 g, 72% yield). ¹H NMR (400 MHz,DMSO-d6) δ ppm 10.57-10.63 (br, 1H), 8.84 (d, J=2.2 Hz, 1H), 8.74-8.78(m, 1H), 8.50 (d, J=5.3 Hz, 1H), 8.07-8.12 (m, 1H), 7.55-7.59 (m, 1H),7.31-7.37 (m, 1H), 7.17-7.28 (m, 3H), 6.92 (d, J=5.3 Hz, 1H), 3.24-3.34(m, 1H), 1.34 (d, J=6.8 Hz, 6H). MS (ES+): 472 [M+H]⁺.

Step B:N-{3-[2-(1-Methylethyl)-5-(2-{[2-(methylsulfonyl)ethyl]amino}-4-pyrimidinyl)-1,3-thiazol-4-yl]phenyl}-3-pyridinesulfonamide

Following a procedure analogous to the procedure described in Example 1using 2-aminoethyl-methyl-sulfone (391 mg, 3.18 mmol) andN-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]phenyl}-3-pyridinesulfonamide(150 mg, 0.318 mmol) the title compound was obtained as a white foam (72mg, 41% yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.60 (s, 1H) 8.84 (d,J=1.8 Hz, 1H) 8.76 (dd, J=4.8, 1.3 Hz, 1H) 8.02-8.13 (m, 2H) 7.58 (dd,J=7.9, 4.8 Hz, 1H) 7.46 (t, J=5.3 Hz, 1H) 7.32 (t, J=8.2 Hz, 1H)7.12-7.27 (m, 3H) 5.98-6.16 (m, 1H) 3.64 (dd, J=2.4, 1.3 Hz, 2H)3.31-3.37 (m, 2H) 3.16-3.29 (m, 1H) 2.99 (s, 3H) 1.33 (d, J=6.9 Hz, 6H).MS (ESI): 559.0 [M+H]⁺.

Example 34N-{2-Fluoro-5-[2-(1-methylethyl)-5-(2-{[2-(methylsulfonyl)ethyl]amino}-4-pyrimidinyl)-1,3-thiazol-4-yl]phenyl}-2-furansulfonamidetrifluoroacetic acid salt

Step A:N-{5-[5-(2-Chloro-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2-furansulfonamide

The5-[5-(2-chloro-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}amine(524 mg, 1.50 mmol) was dissolved in DCM (20 mL) and treated withpyridine (0.243 mL, 3.00 mmol). After 5 min, 2-furansulfonyl chloride(250 mg, 1.501 mmol) was added at rt overnight. The reaction mixture wasdiluted with 2N aqueous HCl and extracted with DCM. The DCM layer waswashed with brine and dried over NaSO₄, filtered, added silica gel andconcentrated. The crude product was chromatographed on silica geleluting with 1:1 hexane:(6:4:0.5 Hexane:DCM:EtOAc). The title compoundwas obtained (88 mg, 12% yield). MS (ESI): 479.1[M+H]⁺.

Step B:N-{2-Fluoro-5-[2-(1-methylethyl)-5-(2-{[2-(methylsulfonyl)ethyl]amino}-4-pyrimidinyl)-1,3-thiazol-4-yl]phenyl}-2-furansulfonamidetrifluoroacetic acid salt

Following a procedure analogous to the procedure described in Example 1usingN-{5-[5-(2-chloro-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2-furansulfonamide(85 mg, 0.177 mmol) and 2-aminoethyl-methyl-sulfone (250 mg, 2.03 mmol)the title compound was obtained as a white foam (35 mg, 29% yield) afterpurification by Gilson Acidic HPLC (10 to 90% gradient,Acetonitrile/H2O+TFA; C18 column). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.59(s, 1H), 8.14 (d, J=4.9 Hz, 1H), 7.83-8.01 (m, 1H), 7.41-7.47 (m, 1H),7.35-7.41 (m, 1H), 7.33 (dd, J=7.5, 1.9 Hz, 1H), 7.26 (t, J=9.3 Hz, 1H),6.97 (d, J=3.5 Hz, 1H), 6.57 (dd, J=3.4, 1.7 Hz, 1H), 6.25 (d, J=4.5 Hz,1H), 3.60-3.74 (m, 2H), 3.15-3.40 (m, 3H), 2.97 (s, 3H), 1.32 (d, J=6.9Hz, 6H). MS (ESI) free base: 567.2 [M+H]⁺.

Example 351-Methyl-N-{3-[2-(1-methylethyl)-5-(2-{[2-(methylsulfonyl)ethyl]amino}-4-pyrimidinyl)-1,3-thiazol-4-yl]phenyl}-1H-pyrazole-4-sulfonamidetrifluoroacetic acid salt

Step A:N-{3-[5-(2-Chloro-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]phenyl}-1-methyl-1H-pyrazole-4-sulfonamide

Following a procedure analogous to the procedure described inIntermediate 14 using3-[5-(2-chloro-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]aniline(600 mg, 1.8 mmol) and 1-methyl-1H-pyrazole-4-sulfonyl chloride (0.49 g,2.7 mmol) the title compound was obtained (500 mg, 58.6% yield). ¹H NMR(400 MHz, CDCl₃) δ ppm 8.31 (d, J=5.3 Hz, 1H), 7.72 (d, J=0.9 Hz, 1H),7.65 (d, J=0.9 Hz, 1H), 7.32-7.37 (m, 1H), 7.21-7.30 (m, 2H), 6.94 (S,1H), 6.92 (d, J=5.3 Hz, 1H), 3.86 (S, 3H), 3.31-3.41 (m, 1H), 1.44 (d,J=6.8, 6H). MS (ES+): 475 [M+H]⁺.

Step B:1-Methyl-N-{3-[2-(1-methylethyl)-5-(2-{[2-(methylsulfonyl)ethyl]amino}-4-pyrimidinyl)-1,3-thiazol-4-yl]phenyl}-1H-pyrazole-4-sulfonamidetrifluoroacetic acid salt

Following a procedure analogous to the procedure described in Example 1usingN-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]phenyl}-1-methyl-1H-pyrazole-4-sulfonamide(100 mg, 0.211 mmol) and 2-aminoethyl-methyl-sulfone (259 mg, 2.105mmol) the title compound was obtained (75 mg, 50% yield) as a yellowfoam after purification by Gilson Acidic HPLC (10 to 90% gradient,Acetonitrile/H2O+TFA; C18 column). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.21(s, 1H), 8.18 (s, 1H), 8.07 (d, J=5.0 Hz, 1H), 7.62 (s, 1H), 7.45 (br.s., 1H), 7.31 (t, J=7.9 Hz, 1H), 7.16-7.24 (m, 2H), 7.14 (d, J=7.6 Hz,1H), 6.15 (d, J=4.6 Hz, 1H), 3.77 (s, 3H), 3.51-3.69 (m, 2H), 3.17-3.36(m, 3H), 2.97 (s, 3H), 1.32 (d, J=6.9, 6H). MS (ESI) free base: 562.1[M+H]⁺.

Example 36N-{2-Fluoro-5-[2-(1-methylethyl)-5-(2-{[3-(methylsulfonyl)propyl]amino}-4-pyrimidinyl)-1,3-thiazol-4-yl]phenyl}-1-methyl-1H-imidazole-4-sulfonamide

Step A:N-{5-[5-(2-Chloro-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-1-methyl-1H-imidazole-4-sulfonamide

{5-[5-(2-chloro-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}amine(160 mg, 0.459 mmol) was dissolved in DMF (3 mL) and added pyridine(0.074 mL; 0.917 mmol). The reaction was stirred 5 min and added1-methylimidazole-4-sulfonyl chloride (83 mg, 0.459 mmol). The reactionmixture was heated at 45° C. for two days. The reaction mixture wascooled to rt, added silica gel, and concentrated. The crude product waschromatographed on silica gel eluting with 100% DCM to 100% EtOAc toobtained the title compound as a white solid (150 mg, 66% yield). ¹H NMR(400 MHz, DMSO-d₆) δ ppm 10.12 (br. s., 1H), 8.49 (d, J=5.4 Hz, 1H),7.52-7.83 (m, 2H), 7.51 (d, J=1.8 Hz, 1H), 7.28-7.43 (m, 1H), 7.25 (t,J=9.3 Hz, 1H), 7.05 (d, J=5.3 Hz, 1H), 3.58 (s, 3H), 3.00-3.23 (m, 1H),1.35 (d, J=6.9 Hz, 6H).

Step B:N-{2-Fluoro-5-[2-(1-methylethyl)-5-(2-{[3-(methylthio)propyl]amino}-4-pyrimidinyl)-1,3-thiazol-4-yl]phenyl}-1-methyl-1H-imidazole-4-sulfonamide

Following a procedure analogous to the procedure described in Example 1usingN-{5-[5-(2-chloro-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-methyl-1H-imidazole-4-sulfonamide(75 mg, 0.152 mmol) and [3-(methylthio)propyl]amine (86 mg, 0.817 mmol)the title compound of Step B was obtained as a golden oil (76 mg, 89%yield). MS (ESI): 561.4 [M+H]⁺.

Step C:N-{2-Fluoro-5-[2-(1-methylethyl)-5-(2-{[3-(methylsulfonyl)propyl]amino}-4-pyrimidinyl)-1,3-thiazol-4-yl]phenyl}-1-methyl-1H-imidazole-4-sulfonamide

Following a procedure analogous to the procedure described in Example12, Step B using oxone (208 mg, 0.34 mmoles) andN-{2-Fluoro-5-[2-(1-methylethyl)-5-(2-{[3-(methylthio)propyl]amino}-4-pyrimidinyl)-1,3-thiazol-4-yl]phenyl}-1-methyl-1H-imidazole-4-sulfonamide[76 mg, 0.135 mmoles (obtained from a compilation of multiple batchesprepared in a manner analogous to Step B)] the title compound wasobtained as a white solid (40 mg; 50% yield). ¹H NMR (400 MHz, DMSO-d₆)δ ppm 10.07 (s, 1H), 8.06 (d, J=5.2 Hz, 1H), 7.66 (d, J=6.3 Hz, 2H),7.39-7.55 (m, 1H), 7.37 (t, J=5.6 Hz, 1H), 7.11-7.31 (m, 2H), 6.06-6.22(m, 1H), 3.57 (s, 3H), 3.30-3.39 (m, 2H), 3.20-3.26 (m, 1H), 3.04-3.16(m, 2H), 2.92 (s, 3H), 1.85-1.97 (m, 2H), 1.32 (d, J=6.9 Hz, 6H). MS(ESI): 593.9 [M+H]⁺.

Example 37N-{3-[2-(1-Methylethyl)-5-(2-{[2-(methylsulfonyl)ethyl]amino}-4-pyrimidinyl)-1,3-thiazol-4-yl]phenyl}-4-morpholinesulfonamidetrifluoroacetic acid salt

Step A:N-{3-[5-(2-Chloro-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]phenyl}-4-morpholinesulfonamide

To a solution of3-[5-(2-chloro-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]aniline(1.5 g, 4.5 mmol) in pyridine (15 mL) was added morpholine-4-sulfonylchloride (1.26 g, 6.8 mmol). The reaction was stirred at rt for 12 h.Then the reaction was washed with water (50 mL), and extracted with DCM(2×50 mL). The organic layer was washed with brine, dried over anhydrousNaSO₄, filtrated and concentrated under reduced pressure to give thecrude product, which was purified by column chromatography on silica gel(DCM:EtOAc 60:1) to afford the title compound of Step A (297 mg, 13.8%yield). ¹H NMR (400 MHz, CDCl₃) δ ppm 8.30 (d, J=5.3 Hz, 1H), 7.27-7.36(m, 2H), 7.21-7.26 (m, 2H), 6.98 (d, J=5.3 Hz, 1H), 3.58-3.64 (m, 4H),3.22-3.33 (m, 1H), 3.14-3.21 (m, 4H), 1.40 (d, J=7.0 Hz, 6H). MS (ES+):480 [M+H]⁺.

Step B:N-{3-[2-(1-Methylethyl)-5-(2-{[2-(methylsulfonyl)ethyl]amino}-4-pyrimidinyl)-1,3-thiazol-4-yl]phenyl}-4-morpholinesulfonamidetrifluoroacetic acid salt

Following a procedure analogous to the procedure described in Example 1usingN-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]phenyl}-4-morpholinesulfonamide(92 mg, 0.192 mmol) and 2-aminoethyl-methyl-sulfone (189 mg, 1.533 mmol)the title compound was obtained (79 mg, 61% yield) as a light yellowsolid after purification by Gilson Acidic HPLC (10 to 90% gradient,Acetonitrile/H₂O+TFA; C18 column). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.09(s, 1H), 8.12 (d, J=4.9 Hz, 1H), 7.46 (br. s., 1H), 7.35 (t, J=7.9 Hz,1H), 7.30 (s, 1H), 7.25 (d, J=8.2 Hz, 1H), 7.19 (d, J=7.6 Hz, 1H), 6.28(d, J=4.8 Hz, 1H), 3.63 (d, J=6.0 Hz, 2H), 3.41-3.53 (m, 4H), 3.21-3.40(m, 3H), 2.99-3.05 (m, 4H), 2.98 (s, 3H), 1.33 (d, J=6.9 Hz, 6H). MS(ESI) free base: 566.2 [M+H]⁺.

Example 385-Fluoro-N-[3-(2-(1-methylethyl)-5-{2-[(2-methylpropyl)amino]-4-pyrimidinyl}-1,3-thiazol-4-yl)phenyl]-2-(methyloxy)benzenesulfonamide

Step A:N-{3-[5-(2-Chloro-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]phenyl}-5-fluoro-2-(methyloxy)benzenesulfonamide

Following a procedure analogous to the procedure described inIntermediate 14 using3-[5-(2-chloro-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]aniline(309 mg, 0.934 mmol) and 5-fluoro-2-(methyloxy)benzenesulfonyl chloride(210 mg, 0.934 mmol) the title compound of Step A was obtained as awhite solid. (381 mg, 79% yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.34(s, 1H), 8.42 (d, J=5.3 Hz, 1H), 7.39-7.54 (m, 2H), 7.23-7.37 (m, 1H),7.09-7.23 (m, 4H), 6.87 (d, J=5.3 Hz, 1H), 3.79 (s, 3H), 3.29-3.38 (m,1H), 1.33 (d, J=6.9 Hz, 6H).

Step B:5-Fluoro-N-[3-(2-(1-methylethyl)-5-{2-[(2-methylpropyl)amino]-4-pyrimidinyl}-1,3-thiazol-4-yl)phenyl]-2-(methyloxy)benzenesulfonamide

Following a procedure analogous to the procedure described in Example18, Step B usingN-{3-[5-(2-Chloro-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]phenyl}-5-fluoro-2-(methyloxy)benzenesulfonamide(89 mg, 0.171 mmol) and isobutylamine (0.172 mL, 1.715 mmol) the titlecompound was obtained as a yellow foam (58 mg, 61% yield). ¹H NMR (400MHz, DMSO-d₆) δ ppm 10.27 (s, 1H), 7.92 (d, J=5.1 Hz, 1H), 7.36-7.52 (m,2H), 7.29 (t, J=5.9 Hz, 1H), 7.09-7.26 (m, 4H), 7.06 (d, J=7.5 Hz, 1H),5.92 (dd, J=6.6, 0.9 Hz, 1H), 3.79 (s, 3H), 3.15-3.27 (m, 1H), 2.99 (d,J=0.9 Hz, 2H), 1.71-1.87 (m, 1H), 1.31 (d, J=6.9 Hz, 6H), 0.82 (d, J=6.7Hz, 6H). MS (ESI): 556.0 [M+H]⁺.

Example 39N-[2-Fluoro-3-(2-(1-methylethyl)-5-{2-[(2-methylpropyl)amino]-4-pyrimidinyl}-1,3-thiazol-4-yl)phenyl]-2-methylbenzenesulfonamide

Step A:N-{3-[5-(2-Chloro-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2-methylbenzenesulfonamide

Following a procedure analogous to the procedure described inIntermediate 14 using3-(5-(2-chloropyrimidin-4-yl)-2-isopropylthiazol-4-yl)-2-fluoroaniline(350 mg, 1.003 mmol) and 2-methylbenzenesulfonyl chloride (0.145 mL,1.00 mmol) the title compound of Step A was obtained as a yellow solid(140 mg, 28% yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.37 (s, 1H),8.35-8.65 (m, 1H), 7.70 (d, J=7.8 Hz, 1H), 7.11-7.50 (m, 6H), 6.73 (d,J=5.2 Hz, 1H), 3.35-3.41 (m, 1H), 2.54 (s, 3H), 1.34 (d, J=6.9 Hz, 6H).

Step B:N-[2-Fluoro-3-(2-(1-methylethyl)-5-{2-[(2-methylpropyl)amino]-4-pyrimidinyl}-1,3-thiazol-4-yl)phenyl]-2-methylbenzenesulfonamide

Following a procedure analogous to the procedure described in Example18, Step B usingN-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2-methylbenzenesulfonamide(70 mg, 0.139 mmol) and isobutylamine (0.140 mL, 1.39 mmol) the titlecompound was obtained as a light yellow solid (45 mg, 60% yield). ¹H NMR(400 MHz, DMSO-d₆) δ ppm 10.37 (s, 1H), 8.01 (d, J=5.1 Hz, 1H),7.67-7.85 (m, 1H), 7.41-7.59 (m, 1H), 7.28-7.42 (m, 4H), 7.15-7.28 (m,2H), 5.64-5.89 (m, 1H), 3.23-3.30 (m, 1H), 2.88-3.13 (m, 2H), 2.57 (s,3H), 1.72-1.91 (m, 1H), 1.34 (d, J=6.8 Hz, 6H), 0.86 (d, J=6.1 Hz, 6H).MS (ESI): 540.0 [M+H]⁺.

Example 40N-{2-Fluoro-3-[2-(1-methylethyl)-5-(2-{[1-(methylsulfonyl)-4-piperidinyl]amino}-4-pyrimidinyl)-1,3-thiazol-4-yl]phenyl}-1,3-thiazole-2-sulfonamide

Step A:N-{3-[5-(2-Chloro-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}1,3-thiazole-2-sulfonamide

Following a procedure analogous to the procedure described inIntermediate 14 using3-(5-(2-chloropyrimidin-4-yl)-2-isopropylthiazol-4-yl)-2-fluoroaniline(2.5 g, 7.2 mmol) and thiazole-2-sulfonyl chloride (1.45 g, 7.88 mmol)the title compound of Step A was obtained (1.05 g, 30.0% yield). ¹H NMR(400 MHz, DMSO-d6) δ ppm 11.01 (br. s., 2H), 8.58 (d, J=5.2 Hz, 1H),8.09 (d, J=3.2 Hz, 1H), 8.01 (d, J=2.8 Hz, 1H), 7.49-7.40 (m, 1H),7.31-7.25 (m, 1H), 6.88 (d, J=5.6 Hz, 1H), 3.35-3.30 (m, 1H), 1.36 (d,J=6.8 Hz, 6H). MS (ES+): 496 [M+H]⁺.

Step B:N-{2-Fluoro-3-[2-(1-methylethyl)-5-(2-{[1-(methylsulfonyl)-4-piperidinyl]amino}-4-pyrimidinyl)-1,3-thiazol-4-yl]phenyl}-1,3-thiazole-2-sulfonamide

Following a procedure analogous to the procedure described in Example 1usingN-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-3-thiazole-2-sulfonamide(70 mg, 0.141 mmol) and 1-(methylsulfonyl)-4-piperidinamine (126 mg,0.706 mmol) the title compound was obtained as an off-white solid (43mg, 48% yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.96 (d, J=1.6 Hz, 1H),8.08 (d, J=4.3 Hz, 1H), 7.71-8.02 (m, 2H), 7.39-7.49 (m, 1H), 7.25 (d,J=7.7 Hz, 1H), 6.95-7.23 (m, 2H), 5.90-6.23 (m, 1H), 3.64-3.94 (m, 1H),3.37-3.64 (m, 3H), 3.24 (br. s., 0H), 2.65-2.93 (m, 5H), 1.79-2.00 (m,2H), 1.39-1.59 (m, 2H), 1.24-1.40 (m, 6H). MS (ESI): 638.1 [M+H]⁺.

Example 41N-{2-Fluoro-3-[5-(2-{[1-(methylsulfonyl)-4-piperidinyl]amino}-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]phenyl}-2-furansulfonamide

Step A:N-{3-[5-(2-Chloro-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2-furansulfonamide

Following a procedure analogous to the procedure described inIntermediate 14 using3-(5-(2-chloropyrimidin-4-yl)-2-morpholinothiazol-4-yl)-2-fluoroaniline(3.0 g, 7.6 mmol) and furan-2-sulfonyl chloride (1.4 g, 8.4 mmol) thetitle compound of Step A was obtained (2.5 g, 63% yield). ¹H NMR (400MHz, DMSO-d6) δ ppm 8.07 (d, J=5.5 Hz, 1H), 7.59-7.66 (m, 1H), 7.42-7.75(br, 1H), 7.13-7.20 (m, 2H), 7.02 (d, J=5.5 Hz, 1H), 6.93-6.98 (m, 1H),6.37-6.42 (m, 2H), 3.50-3.57 (m, 4H), 3.72-3.78 (m, 4H). MS (ES+): 522[M+H]⁺.

Step B:N-{2-Fluoro-3-[5-(2-{[1-(methylsulfonyl)-4-piperidinyl]amino}-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]phenyl}-2-furansulfonamide

Following a procedure analogous to the procedure described in Example 1usingN-{3-[5-(2-chloro-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2-furansulfonamide(91.2 mg, 0.175 mmol) and 1-(methylsulfonyl)-4-piperidinamine (249 mg,1.398 mmol) the title compound was obtained as a yellow solid (55 mg,48% yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.57 (s, 1H), 7.82-8.02 (m,2H), 7.34 (td, J=7.3, 1.8 Hz, 1H), 7.17-7.29 (m, 2H), 6.95-7.15 (m, 2H),6.54 (dd, J=3.2, 1.7 Hz, 1H), 5.71 (s, 2H), 3.67 (t, J=4.6 Hz, 4H),3.36-3.55 (m, 6H), 2.64-2.95 (m, 5H), 1.86 (d, J=10.3 Hz, 2H), 1.48 (d,J=10.4 Hz 2H). MS (ESI): 664.2 [M+H]⁺.

Example 42N-[2-Fluoro-3-(2-(1-methylethyl)-5-{2-[(2-methylpropyl)amino]-4-pyrimidinyl}-1,3-thiazol-4-yl)phenyl]-3-pyridinesulfonamide

Step A:N-{3-[5-(2-Chloro-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-3-pyridinesulfonamide

Following a procedure analogous to the procedure described inIntermediate 14 using3-(5-(2-chloropyrimidin-4-yl)-2-isopropylthiazol-4-yl)-2-fluoroaniline(3 g, 8.6 mmol) and pyridine-3-sulfonyl chloride (1.68 g, 9.5 mmol) thetitle compound of Step A was obtained (2.1 g, 75.3% yield). ¹H NMR (400MHz, CDCl₃) δ ppm 8.97-9.01 (br, 1H), 8.76-8.79 (m, 1H), 8.35 (d, J=5.3Hz, 1H), 8.08-8.12 (m, 1H), 7.68-7.74 (m, 1H), 7.40-7.44 (m, 1H),7.22-7.34 (m, 3H), 6.69 (d, J=5.3 Hz, 1H), 3.29-3.38 (m, 1H), 1.44 (d,J=6.8 Hz, 6H). MS (ES+): 490 [M+H]⁺.

Step B:N-[2-Fluoro-3-(2-(1-methylethyl)-5-{2-[(2-methylpropyl)amino]-4-pyrimidinyl}-1,3-thiazol-4-yl)phenyl]-3-pyridinesulfonamide

Following a procedure analogous to the procedure described in Example18, Step B usingN-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-3-pyridinesulfonamide(150 mg, 0.306 mmol) and isobutylamine (0.307 mL, 3.06 mmol). the titlecompound was obtained as a white solid (105 mg, 65% yield). ¹H NMR (400MHz, DMSO-d₆) δ ppm 10.53 (s, 1H), 8.83 (d, J=2.2 Hz, 1H), 8.73 (dd,J=4.8, 1.0 Hz, 1H), 8.03-8.13 (m, 1H), 7.99 (d, J=5.1 Hz, 1H), 7.53 (dd,J=8.1, 4.9 Hz, 1H), 7.31-7.41 (m, 1H), 7.09-7.33 (m, 3H), 5.67-5.93 (m,1H), 3.14-3.25 (m, 1H), 2.84-3.09 (m, 2H), 1.69-1.87 (m, 1H), 1.30 (d,J=6.9 Hz, 6H), 0.81 (d, J=5.3 Hz, 6H). MS (ESI): 527.2 [M+H]⁺.

Example 43N-{2-fluoro-3-[5-{2-[(2-methylpropyl)amino]-4-pyrimidinyl}-2-(4-morpholinyl)-1,3-thiazol-4-yl]phenyl}-2-furansulfonamide

Following a procedure analogous to the procedure described in Example18, Step B usingN-{3-[5-(2-chloro-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2-furansulfonamide(150 mg, 0.287 mmol) and isobutylamine (0.288 mL, 2.87 mmol) the titlecompound was obtained as a light yellow solid (88 mg, 55% yield). ¹H NMR(400 MHz, DMSO-d₆) δ ppm 10.56 (s, 1H), 7.77-7.91 (m, 2H), 7.30-7.41 (m,1H), 7.16-7.32 (m, 2H), 7.10 (d, J=1.1 Hz, 1H), 7.03 (d, J=3.4 Hz, 1H),6.54 (dd, J=3.3, 1.7 Hz, 1H), 3.66 (t, J=4.6 Hz, 4H), 3.41 (t, J=4.5 Hz,4H), 2.97 (br. s., 2H), 1.78 (dt, J=13.4, 6.7 Hz, 1H), 0.73-0.87 (m,7H). MS (ESI): 559.0 [M+H]⁺.

Example 442,6-Difluoro-N-[3-(2-(1-methylethyl)-5-{2-[(2-methylpropyl)amino]-4-pyrimidinyl}-1,3-thiazol-4-yl)-2-(methyloxy)phenyl]benzenesulfonamide

Step A: Methyl 2-hydroxy-3-nitrobenzoate

To a solution of 2-hydroxy-3-nitrobenzoic acid (25 g, 136 mmol) in DMF(125 mL) was added K₂CO₃ (37.8 g, 273 mmol). Then dimethyl sulfate (48.2g, 382 mmol) was added dropwise to the mixture at rt. The mixture wasstirred at rt overnight. Then the reaction was quenched by the additionof the saturated aqueous NH₄Cl (800 mL) at 0° C. The reaction mixturewas extracted with EtOAc (500 mL×2). The combined organic layers werewashed with water successively, dried over Na₂SO₄, filtered andconcentrated under reduced pressure to give the title compound of Step A(26.8 g, 99.6% yield). ¹H NMR (400 MHz, CDCl₃) δ ppm 8.10-8.18 (m, 2H),7.97-8.03 (br, 1H), 6.95-7.03 (m, 1H), 4.00 (s, 3H).

Step B: Methyl 2-methoxy-3-nitrobenzoate

To a solution of methyl 2-hydroxy-3-nitrobenzoate (26.8 g, 136 mmol) inDMF (200 mL) was added K₂CO₃ (61 g, 440 mmol). Then iodomethane (62 g,436 mmol) was added dropwise to the mixture at rt. The mixture wasstirred at 45° C. for 5 h. Then the mixture was cooled to rt and waterwas added. The reaction mixture was extracted with EtOAc (500 mL×2). Thecombined organic layers were washed with water successively, dried overNa₂SO₄, filtered and concentrated under reduced pressure to give thetitle compound of Step B (28.4 g, 98.8% yield). ¹H NMR (400 MHz,DMSO-d6) δ ppm 8.10 (dd, J=1.8 Hz, 8.4 Hz, 1H), 8.00 (dd, J=1.3 Hz, 8.2Hz, 1H), 7.40 (dd, J=8.2 Hz, 8.4 Hz, 1H), 3.87 (s, 3H), 3.85 (s, 3H).

Step C: Methyl 3-amino-2-methoxybenzoate

To a solution of methyl 2-methoxy-3-nitrobenzoate (28.4 g, 134 mmol) inMeOH (150 mL) was added Raney Ni (3 g). The mixture was stirred under H₂atmosphere (50 psi/25° C.) for 3.5 h. The catalyst was filtered, and thefiltrate was concentrated under the reduced pressure to dryness to givethe crude product, which was purified by recrystallization in EtOAc toafford the title compound of Step C, methyl 3-amino-2-methoxybenzoate(23.5 g, 96.4% yield). ¹H NMR (400 MHz, DMSO-d6) δ ppm 6.80-6.93 (m,3H), 5.10-5.25 (br, 2H), 3.78 (s, 3H), 3.67 (s, 3H).

Step D: Methyl2-(methyloxy)-3-{[(2-propen-1-yloxy)carbonyl]amino}benzoate

To a solution of methyl 3-amino-2-methoxybenzoate (94 g, 580 mmol) (fromcomposite batches prepared as described above) in THF (1800 mL),saturated NaHCO₃ (60.9 g, 725 mmol) was added. Then 2-propen-1-ylchloridocarbonate (83.7 g, 696 mmol) was added dropwise at 0° C. Themixture was stirred at rt for 2 h. The solution was extracted with EtOAc(700 mL×3). The combined organic layers were washed with water and brinesuccessively, dried over Na₂SO₄, filtered and concentrated under reducedpressure to give the title compound of Step D (123 g, 80% yield), whichwas used in the next step directly. ¹H NMR (400 MHz, CDCl₃) δ ppm8.25-8.35 (m, 1H), 7.49-7.53 (m, 1H), 7.36-7.42 (br, 1H), 7.10-7.18 (m,1H), 5.91-6.07 (m, 1H), 5.75-5.90 (m, 2H), 4.63-4.70 (m, 2H), 3.92 (s,3H), 3.86 (s, 3H).

Step E:2-Propen-1-yl[3-[(2-chloro-4-pyrimidinyl)acetyl]-2-(methyloxy)phenyl]carbamate

To a solution of methyl2-(methyloxy)-3-{[(2-propen-1-yloxy)carbonyl]amino}benzoate (123 g, 464mmol,) in dry THF (800 mL) at −10° C., LiHMDS (1M in THF, 1440 mmol,1440 mL) was added dropwise and the solution was allowed to stir for 1 hat 0° C. A solution of 2-chloro-4-methylpyrimidine (72 g, 560 mmol) inTHF (150 mL) was then added dropwise to the solution of ester and baseat 0° C. over 20 min. The solution was allowed to stir 1 h at rt. TLCshowed the reaction was complete. The reaction was quenched by additionof the saturated aqueous NH₄Cl (800 mL) at 0° C. The reaction mixturewas extracted with EtOAc (1 L×3). The combined organic layers werewashed with water and brine successively, dried over Na₂SO₄, filteredand concentrated under reduced pressure to give the crude product, whichwas purified by flash column on silica gel, eluting with DCM. Thissolution was evaporated to obtain a solid. The orange solid wastriturated with a small amount of EtOAc and filtered, rinsing withdiethyl ether to give the title compound of Step E (109.9 g, 67.8%yield). ¹H NMR (400 MHz, CDCl₃) δ ppm 13.64-13.68 (br, 1H), 8.38 (d,J=5.3 Hz, 1H), 8.15-8.21 (m, 1H), 7.31-7.39 (m, 2H), 7.15-7.18 (m, 1H),6.87 (d, J=5.3 Hz, 1H), 6.19 (s, 1H), 5.92-6.15 (m, 1H), 5.23-5.40 (m,2H), 4.66-4.70 (m, 2H), 3.76 (s, 3H).

Step F:2-Propen-1-yl[3-[5-(2-chloro-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]-2-(methyloxy)phenyl]carbamate

To a solution of2-propen-1-yl[3-[(2-chloro-4-pyrimidinyl)acetyl]-2-(methyloxy)phenyl]carbamate(15.4 g, 42 mmol) in DCM (150 mL), NBS (7.6 g, 42 mmol) was added andthe solution was allowed to stir at rt for 30 min. The reaction mixturewas then concentrated in vacuo and the resulting oil was diluted withDMSO (150 mL) and 2-methylpropanethioamide (6.6 g 63.8 mmol) was addedat once. The reaction was complete after stirring 1 h at rt. Thereaction mixture was diluted with EtOAc and organic layer was washedwith water and brine successively, dried over Na₂SO₄, filtered andconcentrated under reduced pressure to give the crude product, which waspurified by column chromatography on silica gel (DCM:petroleum ether2:1) to afford the title compound of Step F (12.1 g, 63.8% yield) whichwas used directly in the next step.

Step G:3-[5-(2-Chloro-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]-2-(methyloxy)aniline

To the solution of2-propen-1-yl[3-[5-(2-chloro-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]-2-(methyloxy)phenyl]carbamate(12.1 g, 22.5 mmol) in DCM (200 mL), acetic acid (3.8 mL, 66.6 mmol),Pd(PPh₃)₂Cl₂ (0.45 g, 0.56 mmol) were added. Then tri-n-butyl tinhydride (8.5 mL, 33 mmol) was added dropwise to the mixture at 0° C. Themixture was stirred at rt for 30 min. The reaction was quenched by addedthe saturated NaHCO₃ (200 mL) slowly. The two layers were separated. Theaqueous layer was extracted with DCM (200 mL×2). The combined organiclayers were washed with water and brine successively, dried over Na₂SO₄,filtered and concentrated under reduced pressure to give the crudeproduct, which was washed with petroleum ether (500 mL) to afford thetitle compound of Step G (10 g, 60.8% yield), which was used directly inthe next step.

Step H:N-[3-[5-(2-Chloro-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]-2-(methyloxy)phenyl]-2,6-difluorobenzenesulfonamide

To a solution of3-[5-(2-chloro-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]-2-(methyloxy)aniline(10 g, 28 mmol), in DCM (100 mL) was added pyridine (6.6 g, 83.7 mmol)and the mixture was cooled to 0° C. 2,6-Difluorobenzene-1-sulfonylchloride (5.9 g, 27.9 mmol) in DCM (100 mL) was added dropwise to themixture. The reaction was stirred at rt for 4 h. Then the reaction waswashed with water (200 mL), and extracted with DCM (2×200 mL). Theorganic layer was washed with brine, dried over anhydrous NaSO₄,filtrated and concentrated under reduced pressure to give the crudeproduct, which was purified by column chromatography on silica gel(petroleum ether:DCM 1:1) to afford the title compound of Step H (8.7 g,58.2% yield). ¹H NMR (400 MHz, CDCl₃) δ ppm 8.21 (d, J=5.6 Hz, 1H),7.70-7.75 (m, 1H), 7.63-7.67 (br, 1H), 7.46-7.55 (m, 1H), 7.15-7.19 (m,2H), 6.95-7.03 (m, 2H), 6.58 (d, J=5.6 Hz, 1H), 3.35-3.40 (m, 4H), 1.44(d, J=6.4 Hz, 6H). m/z (ES+): 537 [M+H]⁺.

Step I:2,6-Difluoro-N-[3-(2-(1-methylethyl)-5-{2-[(2-methylpropyl)amino]-4-pyrimidinyl}-1,3-thiazol-4-yl)-2-(methyloxy)phenyl]benzenesulfonamide

Following a procedure analogous to the procedure described in Example 1usingN-[3-[5-(2-chloro-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]-2-(methyloxy)phenyl]-2,6-difluorobenzenesulfonamide(150 mg, 0.279 mmol) and isobutylamine (0.140 mL, 1.397 mmol) the titlecompound was obtained as an off-white foam (86.3 mg, 27% yield). ¹H NMR(400 MHz, DMSO-d₆) δ ppm 10.37 (s, 1H), 7.94 (d, J=4.9 Hz, 1H),7.54-7.73 (m, 1H), 7.37 (d, J=7.3 Hz, 1H), 7.15-7.32 (m, 3H), 6.99-7.17(m, 2H), 5.74 (dd, J=2.2, 1.1 Hz, 1H), 3.24-3.28 (m, 1H), 3.12 (s, 3H),3.01 (br. s., 2H), 1.81 (dt, J=13.3, 6.6 Hz, 1H), 1.31 (d, J=6.8 Hz,6H), 0.85 (d, J=6.6 Hz, 6H). MS (ESI): 574.2 [M+H]⁺.

Example 45N-{2-Fluoro-3-[5-{2-[(2-methylpropyl)amino]-4-pyrimidinyl}-2-(4-morpholinyl)-1,3-thiazol-4-yl]phenyl}-3-pyridinesulfonamide

Step A:N-{3-[5-(2-Chloro-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-3-pyridinesulfonamide

Following a procedure analogous to the procedure described inIntermediate 14, using3-(5-(2-chloropyrimidin-4-yl)-2-morpholinothiazol-4-yl)-2-fluoroaniline(3 g, 7.7 mmol) and pyridine-3-sulfonyl chloride (1.49 g, 8.4 mmol) thetitle compound of Step A was obtained (2.9 g, 71.5% yield). ¹H NMR (400MHz, DMSO-d6) δ ppm 10.55-10.60 (br, 1H), 8.82-8.86 (m, 1H), 8.72-8.76(m, 1H), 8.30 (d, J=5.3 Hz, 1H), 8.07-8.13 (m, 1H), 7.51-7.52 (m, 1H),7.39-7.47 (m, 1H), 7.27-7.40 (m, 2H), 6.47 (d, J=5.3 Hz, 1H), 3.47-3.57(m, 4H), 3.67-3.75 (m, 4H). MS (ES+): 533 [M+H]⁺.

Step B:N-{2-Fluoro-3-[5-{2-[(2-methylpropyl)amino]-4-pyrimidinyl}-2-(4-morpholinyl)-1,3-thiazol-4-yl]phenyl}-3-pyridinesulfonamide

Following a procedure analogous to the procedure described in Example18, Step B, usingN-{3-[5-(2-chloro-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-3-pyridinesulfonamide(155 mg, 0.291 mmol) and isobutylamine (0.292 mL, 2.91 mmol) the titlecompound was obtained as a yellow foam (83 mg, 50% yield). ¹H NMR (400MHz, DMSO-d₆) δ ppm 10.53 (s, 1H), 8.83 (d, J=2.3 Hz, 1H), 8.73 (dd,1H), 8.03-8.13 (m, 1H), 7.83 (d, J=5.2 Hz, 1H), 7.53 (dd, J=8.1, 4.9 Hz,1H), 7.31-7.44 (m, 1H), 7.17-7.34 (m, 2H), 7.09 (d, J=1.4 Hz, 1H),5.39-5.65 (m, 1H), 3.66 (t, J=4.6 Hz, 4H), 3.36-3.49 (m, 4H), 2.82-3.14(m, 2H), 1.77 (dt, J=13.3, 6.7 Hz, 1H), 0.82 (d, J=6.6 Hz, 6H). MS(ESI): 570.1 [M+H]⁺.

Example 46N-[5-(2-(1,1-Dimethylethyl)-5-{2-[(2-methylpropyl)amino]-4-pyrimidinyl}-1,3-thiazol-4-yl)-2-fluorophenyl]-2,6-difluorobenzenesulfonamide

Following a procedure analogous to the procedure described in Example18, Step B usingN-{5-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide(200 mg, 0.371 mmol) and isobutylamine (0.372 mL, 3.71 mmol) the titlecompound was obtained as an off-white foam (90 mg, 42% yield). ¹H NMR(400 MHz, DMSO-d₆) δ ppm 10.88 (s, 1H), 8.03 (d, J=5.1 Hz, 1H),7.61-7.78 (m, 1H), 7.26-7.42 (m, 3H), 7.14-7.27 (m, 3H), 6.04-6.22 (m,1H), 2.89-3.07 (m, 2H), 1.72-1.85 (m, 1H), 1.37 (s, 9H), 0.82 (d, J=6.4Hz, 6H). MS (ESI): 576.2 [M+H]⁺.

Example 472,6-Difluoro-N-{2-(methyloxy)-3-[5-{2-[(2-methylpropyl)amino]-4-pyrimidinyl}-2-(4-morpholinyl)-1,3-thiazol-4-yl]phenyl}benzenesulfonamide

Step A:2-Propen-1-yl[3-[5-(2-chloro-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]-2-(methyloxy)phenyl]carbamate

To a solution of2-propen-1-yl[3-[(2-chloro-4-pyrimidinyl)acetyl]-2-(methyloxy)phenyl]carbamate(30 g, 82.9 mmol) in DCM (300 mL), NBS (14.8 g, 82.9 mmol) was added andthe solution was allowed to stir at rt for 30 min. The reaction mixturewas then concentrated on the rotovap and the resulting oil was dilutedwith DMSO (240 mL) and 4-morpholinecarbothioamide (14.8 g 101 mmol) wasadded at once. The reaction was complete after stirring 1 h at rt. Thecombined organic layers were washed with water and brine successively,dried over Na₂SO₄, filtered and concentrated under reduced pressure togive the crude product which was purified by column chromatography onsilica gel (DCM:petroleum ether 2:1) to afford the product of Step A (40g, 98.8% yield) which was used directly in the next step.

Step B:3-[5-(2-Chloro-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]-2-(methyloxy)aniline

To a solution of2-propen-1-yl[3-[5-(2-chloro-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]-2-(methyloxy)phenyl]carbamate(40 g, 99 mmol) in DCM (500 mL), acetic acid (11.3 mL, 197 mmol) andPd(PPh₃)₂Cl₂ (1.3 g, 1.64 mmol) were added. Then tri-n-butyl tin hydride(37.3 mL, 145 mmol) was added dropwise to the mixture at 0° C. Themixture was stirred at rt for 30 min. The reaction was quenched by slowaddition of saturated NaHCO₃ (200 mL). The two layers were separated.The aqueous layer was extracted with DCM (400 mL×2). The combinedorganic layers were washed with water and brine successively, dried overNa₂SO₄, filtered and concentrated under reduced pressure to give thecrude product, which was washed with petroleum ether (500 mL) to affordthe title compound of Step B (26.1 g, 79.1% yield). ¹H NMR (400 MHz,CDCl₃) δ ppm 8.10 (d, J=5.5 Hz, 1H), 7.01 (dd, J=7.5 Hz, 8.1 Hz, 1H),6.83 (dd, J=1.5 Hz, 8.2 Hz, 1H), 6.68 (dd, J=1.5 Hz, 7.5 Hz, 1H), 6.61(d, J=5.5 Hz, 1H), 3.86-3.95 (br, 2H), 3.78-3.82 (m, 4H), 3.58-3.63 (m,4H), 3.56 (s, 3H).

Step C:N-[3-[5-(2-Chloro-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]-2-(methyloxy)phenyl]-2,6-difluorobenzenesulfonamide

Following a procedure analogous to the procedure described inIntermediate 14 using3-(5-(2-chloropyrimidin-4-yl)-2-morpholinothiazol-4-yl)-2-methoxyaniline(26.1 g, 64.7 mmol) and 2,6-difluorobenzene-1-sulfonyl chloride (13.8 g,64.7 mmol) the title compound of Step C was obtained (10.2 g, 27.2%yield). ¹H NMR (400 MHz, DMSO-d6) δ ppm 8.23 (d, J=5.5 Hz, 1H),7.62-7.71 (m, 1H), 7.38-7.45 (m, 1H), 7.15-7.30 (m, 4H), 6.40 (d, J=5.5Hz, 1H), 3.67-3.78 (m, 4H), 3.50-3.61 (m, 4H), 3.18 (s, 3H). MS (ES+):580 [M+H]⁺.

Step D:2,6-Difluoro-N-{2-(methyloxy)-3-[5-{2-[(2-methylpropyl)amino]-4-pyrimidinyl}-2-(4-morpholinyl)-1,3-thiazol-4-yl]phenyl}benzenesulfonamide

Following a procedure analogous to the procedure described in Example18, Step B usingN-[3-[5-(2-chloro-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]-2-(methyloxy)phenyl]-2,6-difluorobenzenesulfonamide(150 mg, 0.259 mmol) and isobutylamine (0.259 mL, 2.59 mmol) the titlecompound was obtained as a yellow solid (17.8 mg, 11% yield). ¹H NMR(400 MHz, DMSO-d₆) δ ppm 10.31 (s, 1H), 7.78 (d, J=5.3 Hz, 1H),7.59-7.70 (m, 1H), 7.33 (dd, J=7.9, 1.5 Hz, 1H), 7.20 (t, J=9.1 Hz, 2H),6.97-7.15 (m, 3H), 5.53 (d, J=5.3 Hz, 1H), 3.66 (t, J=4.7 Hz, 4H), 3.40(t, J=4.6 Hz, 4H), 3.20 (s, 3H), 2.99 (t, J=6.3 Hz, 2H), 1.64-1.85 (m,1H), 0.83 (d, J=6.6 Hz, 6H). MS (ESI): 617.2 [M+H]⁺.

Example 48N-{3-[5-(2-Amino-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}cyclohexanesulfonamide

Step A:N-{3-[5-(2-Chloro-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}cyclohexanesulfonamide

3-(5-(2-Chloropyrimidin-4-yl)-2-morpholinothiazol-4-yl)-2-fluoroaniline(200 mg, 0.510 mmol) was suspended in pyridine (2 mL) and after 5 min,cyclohexanesulfonyl chloride (0.148 mL 1.021 mmol) was added. Themixture was stirred overnight. Additional cyclohexanesulfonyl chloride(0.100 mL 0.69 mmol) was added and stirred overnight. Silica gel wasadded the reaction mixture and concentrated. The crude product waschromatographed on silica gel eluting with DCM and 9:1 (EtOAc:MeOH). Theproduct was chromatographed again with 9:1 hexane:EtOAc increasing to1:1 gradient. The clean fractions were concentrated to yield the titlecompound of Step A (102 mg, 37% yield). A second reaction was run (46mg, 17% yield) same scale and combined to yield the title compound ofStep A (148 mg). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 9.70 (s, 1H) 8.34 (d,J=5.5 Hz, 1H) 7.55 (td, J=7.6, 2.0 Hz, 2H) 7.14-7.38 (m, 3H) 6.65 (d,J=5.5 Hz, 1H) 3.68 (t, J=4.7 Hz, 4H) 3.52 (t, J=4.6 Hz, 4H) 2.79-3.04(m, 1H) 2.01 (d, J=11.4 Hz, 2H) 1.69 (d, J=13.0 Hz, 3H) 1.47-1.63 (m,2H) 1.26-1.42 (m, 3H) 0.84 (t, J=7.4 Hz, 1H).

Step B:N-{3-[5-(2-Amino-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}cyclohexanesulfonamide

N-[3-(5-(2-Chloro-4-pyrimidinyl)-2-{ethyl[2-(methyloxy)ethyl]amino}-1,3-thiazol-4-yl)-2-fluorophenyl]cyclohexanesulfonamide(148 mg, 0.275 mmol) was suspended in NH₄OH (4 mL) and heated inmicrowave reactor at 120° C. for 48 min. The reaction was diluted withwater and neutralized with 5% aqueous HCl and solid formed. A solid wasdiluted with DCM and water. The organic layer was dried over Na₂SO₄,filtered, added silica gel and concentrated. The crude product waschromatographed on silica gel eluting with 100% DCM to 1:1 [DCM:(9:1EtOAC:MeOH)]. The clean fractions were combined and concentrated. Theproduct was triturated in diethyl ether and filtered to obtain the titlecompound as a yellow powder (58 mg, 41% yield). ¹H NMR (400 MHz,DMSO-d₆) δ ppm 9.67 (s, 1H), 7.87 (d, J=5.3 Hz, 1H), 7.43-7.62 (m, 1H),7.09-7.41 (m, 2H), 6.35-6.74 (m, 2H), 5.80 (d, J=5.3 Hz, 1H), 3.68 (t,J=4.6 Hz, 4H), 3.43 (t, J=4.6 Hz, 4H), 2.81-3.02 (m, 1H), 1.69 (d,J=12.5 Hz, 2H), 1.51 (br. s., 1H), 1.33 (qd, J=12.1, 2.2 Hz, 2H),0.89-1.22 (m, 5H). MS (ESI): 518.9 [M+H]⁺.

Example 49N-{3-[5-(2-Amino-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-1-piperidinesulfonamide

Step A:N-{3-[5-(2-Chloro-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-1-piperidinesulfonamide

Following a procedure analogous to the procedure described inIntermediate 14 using3-(5-(2-chloropyrimidin-4-yl)-2-morpholinothiazol-4-yl)-2-fluoroaniline(200 mg, 0.510 mmol) and 1-piperidinesulfonyl chloride (0.201 mL, 1.531mmol) the title compound of Step A was obtained as a yellow foam (193mg, 41% and 29% yield, repeated twice). ¹H NMR (400 MHz, DMSO-d₆) δ ppm9.72 (s, 1H), 8.15-8.44 (m, 1H), 7.45-7.67 (m, 1H), 7.22-7.42 (m, 2H),6.61 (d, J=5.4 Hz, 1H), 3.68 (t, J=4.7 Hz, 4H), 3.52 (t, J=4.7 Hz, 4H),3.03 (t, J=5.0 Hz, 4H), 1.24-1.66 (m, 6H).

Step B:N-{3-[5-(2-Amino-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-1-piperidinesulfonamide

Following a procedure analogous to the procedure described in Example 21usingN-{3-[5-(2-chloro-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-1-piperidinesulfonamide(190 mg, 0.352 mmol) and NH₄OH (4 mL) in a microwave reactor for 75 minat 120° C., the title compound was obtained an off-white solid (75 mg,41% yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 9.69 (s, 1H) 7.83 (d, J=5.3Hz, 1H) 7.51 (td, J=7.4, 2.2 Hz, 1H) 7.05-7.38 (m, 2H) 6.54 (s, 2H) 5.79(d, J=5.3 Hz, 1H) 3.68 (t, J=4.7 Hz, 4H) 3.43 (t, J=4.6 Hz, 4H), 3.01(t, J=5.0 Hz, 4H) 1.33-1.52 (m, 6H). MS (ESI): 520.0 [M+H]⁺.

Example 50N-{3-[5-(2-Amino-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-4-morpholinesulfonamide

Step A:N-{3-[5-(2-Chloro-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-4-morpholinesulfonamide

Following a procedure analogous to the procedure described inIntermediate 14 using3-(5-(2-chloropyrimidin-4-yl)-2-morpholinothiazol-4-yl)-2-fluoroaniline(150 mg, 0.383 mmol) and 4-morpholinesulfonyl chloride (142 mg, 0.766mmol) the title compound of Step A was obtained as a yellow foam (96 mg,46% yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 9.78-10.01 (m, 1H), 8.34 (d,J=5.5 Hz, 1H), 7.58 (td, J=7.4, 2.4 Hz, 1H), 7.17-7.41 (m, 2H),6.57-6.68 (m, 1H), 3.68 (t, J=4.7 Hz, 4H), 3.42-3.63 (m, 8H), 2.91-3.11(m, 4H).

Step B:N-{3-[5-(2-Amino-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-4-morpholinesulfonamide

Following a procedure analogous to the procedure described in Example 21usingN-{3-[5-(2-chloro-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-4-morpholinesulfonamide(96 mg, 0.177 mmol) in NH₄OH (4 mL), heated in a microwave reactor for40 min at 120° C. the title compound was obtained as a yellow solid (20mg, 22% yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 9.86 (s, 1H), 7.87 (d,J=5.3 Hz, 1H), 7.54 (td, J=6.8, 3.5 Hz, 1H), 7.19-7.31 (m, 2H), 6.54 (s,2H), 5.80 (d, J=5.3 Hz, 1H), 3.68 (t, J=4.4 Hz, 4H), 3.48-3.55 (m, 4H),3.43 (t, J=4.4 Hz, 4H), 2.96-3.03 (m, 4H). MS (ESI): 521.8 [M+H]⁺.

Example 51N-{3-[5-(2-Amino-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}cyclopropanesulfonamide

Step A:N-{3-[5-(2-Chloro-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}cyclopropanesulfonamide

Following a procedure analogous to the procedure described inIntermediate 14 using3-(5-(2-chloropyrimidin-4-yl)-2-morpholinothiazol-4-yl)-2-fluoroaniline(150 mg, 0.383 mmol) and cyclopropanesulfonyl chloride (0.039 mL, 0.383mmol) the title compound of Step A was obtained as a yellow solid (125mg, 66% yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 9.71 (s, 1H), 8.27-8.39(m, 1H), 7.54 (td, J=7.6, 1.7 Hz, 1H), 7.22-7.42 (m, 2H), 6.62-6.72 (m,1H), 5.30 (s, 1H), 3.68 (t, J=4.7 Hz, 4H), 3.52 (t, J=4.6 Hz, 4H),2.59-2.70 (m, 1H), 0.75-0.93 (m, 3H).

Step B:N-{3-[5-(2-Amino-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}cyclopropanesulfonamide

A suspension ofN-{3-[5-(2-chloro-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}cyclopropanesulfonamide(125 mg, 0.252 mmol) and 7M ammonia in MeOH (7 mL, 0.49 mmol) was heatedin a sealed tube to 80° C. for 2 days. The reaction was diluted with DCMand added silica gel and concentrated. The crude product waschromatographed on silica gel eluting with 100% DCM to 1:1 [DCM:(9:1EtOAc:MeOH)]. The clean fractions were concentrated to yield the crudeproduct as a yellow solid (62 mg). The crude product was repurified byreverse phase HPLC (a gradient of acetonitrile:water with 0.1% TFA inboth). The combined clean fractions were concentrated then partitionedbetween DCM and saturated NaHCO₃. The DCM layer was separated and driedover Na₂SO₄. The title compound was obtained as a yellow solid (26 mg,21% yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 9.67 (s, 1H), 7.86 (d, J=5.4Hz, 1H), 7.49 (td, J=7.4, 2.2 Hz, 1H), 7.11-7.38 (m, 2H), 6.53 (s, 2H),5.84 (d, J=5.3 Hz, 1H), 3.68 (t, J=4.7 Hz, 4H), 3.43 (t, J=4.7 Hz, 4H),2.53-2.68 (m, 1H), 0.74-0.92 (m, 4H). MS (ESI): 477.0 [M+H]⁺.

Example 52N-{3-[2-(1-Methylethyl)-5-(2-{[2-(methylsulfonqyl)ethyl]amino}-4-pyrimidinyl)-1,3-thiazol-4-yl]phenyl}cyclopropanesulfonamide

Step A:N-{3-[5-(2-Chloro-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]phenyl}cyclopropanesulfonamide

Following a procedure analogous to the procedure described inIntermediate 14 using3-[5-(2-chloro-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]aniline(1.0 g, 3.03 mmol) and cyclopropanesulfonyl chloride (465 mg, 3.32 mmol)the title compound of Step A was obtained (1.24 g, 94.4% yield). ¹H NMR(400 MHz, CDCl₃) δ ppm 8.30 (d, J=5.3 Hz, 1H), 7.36-7.42 (m, 2H),7.29-7.36 (m, 2H), 7.01 (d, J=5.3 Hz, 1H), 6.91-6.93 (br, 1H), 3.29-3.40(m, 1H), 2.46-2.53 (m, 1H), 1.44 (d, J=7.0 Hz, 6H), 1.12-1.18 (m, 2H),093-1.01 (m, 2H). MS (ES+): 435 [M+H]⁺.

Step B:N-{3-[2-(1-Methylethyl)-5-(2-{[2-(methylsulfonyl)ethyl]amino}-4-pyrimidinyl)-1,3-thiazol-4-yl]phenyl}cyclopropanesulfonamide

Following a procedure analogous to the procedure described in Example 1using 2-aminoethyl-methyl-sulfone (396 mg, 3.22 mmol) andN-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]phenyl}cyclopropanesulfonamide(140 mg, 0.322 mmol) the title compound was obtained as a white solid(41 mg, 23% yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 9.84 (s, 1H), 8.17(d, J=4.0 Hz, 1H), 7.48 (br. s., 1H), 7.37 (s, 2H), 7.33 (s, 1H), 7.27(d, J=7.5 Hz, 1H), 6.34 (d, J=3.5 Hz, 1H), 3.67 (d, J=5.5 Hz, 2H),3.35-3.44 (m, 2H), 3.25-3.30 (m, 1H), 3.02 (s, 3H), 2.54-2.64 (m, 1H),1.37 (d, J=6.8 Hz, 6H), 0.92 (d, J=6.2 Hz, 4H). MS (ESI): 522.2 [M+H]⁺.

Example 53N-{3-[5-(2-Amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-5-fluoro-2-methylbenzenesulfonamide

Step A:4-[4-(3-Amino-2-fluorophenyl)-2-(1,1-dimethylethyl)-1,3-thiazol-5-yl]-2-pyrimidinamine

In a microwave reaction vessel3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluoroaniline(590 mg, 1.626 mmol) was combined with NH₄OH 28-30% (15 mLI, 385 mmol)and 1,4-dioxane (4 mL). The mixture was heated in the microwave for 40min at 130° C. The crude product was then diluted with water (100 mL)followed by extraction with EtOAc (100 mL). The EtOAc layer was washedwith brine then dried over Na₂SO₄. The organics were then filtered andconcentrated to dryness. The crude material was dissolved in DCM (2 mL),injected onto the top of a silica gel column then purified using EtOAcand hexanes. Desired fractions were concentrated to dryness to yield thetitle compound of Step A as a beige powder (490 mg, 1.355 mmol, 83%yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.06 (d, J=5.1 Hz, 1H), 6.97 (t,J=7.8 Hz, 1H), 6.86 (t, J=8.2 Hz, 1H), 6.71 (s, 2H), 6.58 (t, J=6.2 Hz,1H), 6.15 (d, J=5.1 Hz, 1H), 5.26 (s, 2H), 1.42 (s, 9H).

Step B:N-{3-[5-(2-Amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-5-fluoro-2-methylbenzenesulfonamide

Following a procedure analogous to the procedure described inIntermediate 14 using4-[4-(3-amino-2-fluorophenyl)-2-(1,1-dimethylethyl)-1,3-thiazol-5-yl]-2-pyrimidinamine(0.082 g, 0.239 mmol) and 2-methyl 5-fluorobenzenesulfonyl chloride(0.055 g, 0.263 mmol) the title compound was obtained (57 mg, 0.11 mmol,46% yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.48 (s, 1H), 7.91 (d,J=5.3 Hz, 1H), 7.44 (dd, J=8.8, 2.6 Hz, 1H), 7.29-7.42 (m, 3H) 7.16-7.29(m, 2H), 6.71 (s, 2H), 5.73 (d, J=5.1 Hz, 1H), 2.49 (s, 3H), 1.35 (s,9H). MS (ES+): 516 [M+H]+.

Example 54N-{3-[5-(2-Amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2-fluorobenzenesulfonamide

Following a procedure analogous to the procedure described inIntermediate 14 using4-[4-(3-amino-2-fluorophenyl)-2-(1,1-dimethylethyl)-1,3-thiazol-5-yl]-2-pyrimidinamine(0.082 g, 0.239 mmol) and 2-fluorobenzenesulfonyl chloride (0.051 g,0.263 mmol) the title compound,N-{3-[5-(2-amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2-fluorobenzenesulfonamidewas obtained (66 mg, 0.125 mmol, 52.4% yield). ¹H NMR (400 MHz, DMSO-d₆)δ ppm 10.57 (s, 1H), 7.98 (d, J=5.3 Hz, 1H), 7.63-7.74 (m, 2H),7.36-7.46 (m, 2H), 7.32 (t, J=7.4 Hz, 2H), 7.20-7.29 (m, 1H), 6.75 (s,2H), 5.79 (d, J=5.1 Hz, 1H), 1.40 (s, 9H). MS (ES+): 502 [M+H]+.

Example 55N-{2-fluoro-5-[2-(1-methylethyl)-5-(2-{[2-(methylsulfonyl)ethyl]amino}-4-pyrimidinyl)-1,3-thiazol-4-yl]phenyl}cyclopropanesulfonamide

Step A:N-{3-[5-(2-Chloro-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]phenyl}cyclopropanesulfonamide

Following a procedure analogous to the procedure described inIntermediate 14 using{5-[5-(2-chloro-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}amine(283 mg, 0.811 mmol) and cyclopropanesulfonyl chloride (114 mg, 0.811mmol) the title compound was obtained as a white solid (247 mg, 67%yield). MS (ESI): 453.3 [M+H]⁺.

Step B:N-{2-Fluoro-5-[2-(1-methylethyl)-5-(2-{[2-(methylsulfonyl)ethyl]amino}-4-pyrimidinyl)-1,3-thiazol-4-yl]phenyl}cyclopropanesulfonamide

Following a procedure analogous to the procedure described in Example 1usingN-{5-[5-(2-chloro-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}cyclopropanesulfonamide(80 mg, 0.177 mmol) and 2-aminoethyl-methyl-sulfone (174 mg, 1.413 mmol)the title compound was obtained as a white solid (49 mg, 51% yield). ¹HNMR (400 MHz, DMSO-d₆) δ ppm 9.70 (s, 1H), 8.13 (d, J=4.8 Hz, 1H), 7.50(dd, J=7.6, 1.6 Hz, 1H), 7.44 (t, J=4.9 Hz, 1H), 7.25-7.41 (m, 2H), 6.33(d, J=4.5 Hz, 1H), 3.62 (d, J=5.5 Hz, 2H), 3.32 (br. s., 2H), 3.22-3.27(m, 1H), 2.97 (s, 3H), 2.52-2.68 (m, 1H), 1.33 (d, J=6.9 Hz, 6H),0.71-0.96 (m, 4H). MS (ESI): 540.1 [M+H]⁺.

Example 56N-{3-[5-(2-Amino-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide

A suspension ofN-{3-[5-(2-chloro-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide(200 mg, 0.352 mmol) and ammonia in MeOH 7M (7 ml, 49.0 mmol) was heatedin a sealed tube at 80° C. for 48 h. The reaction mixture was evaporatedonto silica gel and chromatographed, 0-50% 1:9 acetone: CHCl₃ in EtOAc.The resulting solid was triturated in MeOH to give the title compound(54 mg, 27% yield). ¹H NMR (400 MHz, DMSO-d6) δ ppm 10.70 (br. s., 1H),7.78 (d, J=5.3 Hz, 1H), 7.40-7.59 (m, 3H), 7.37 (td, J=7.4, 2.0 Hz, 1H),7.14-7.31 (m, 2H), 6.52 (s, 2H), 5.58 (d, J=5.2 Hz, 1H), 3.66 (t, J=4.6Hz, 4H), 3.40 (t, J=4.6 Hz, 4H). MS (ESI): 549.1 [M+H]⁺.

Example 57N-{3-[5-(2-Amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide

Following a procedure analogous to the procedure described in Example51, Step B usingN-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide(200 mg, 0.371 mmol) and ammonia in MeOH 7M (6 ml, 42.0 mmol) andheating to 80° C. overnight, the title compound was obtained as anoff-white solid (158 mg, 78% yield). ¹H NMR (400 MHz, DMSO-d6) δ ppm10.70 (s, 1H), 7.93 (d, J=5.1 Hz, 1H), 7.40-7.56 (m, 3H), 7.35-7.41 (m,1H), 7.28-7.35 (m, 1H), 7.20-7.28 (m, 1H), 6.71 (s, 2H), 5.79 (d, J=5.1Hz, 1H), 1.35 (s, 9H). MS (ESI): 520.2 [M+H]⁺.

Example 58aN-{3-[5-(2-Amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide

Following a procedure analogous to the procedure described in Example51, Step B usingN-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide(196 mg, 0.364 mmol) and ammonia in methanol 7M (8 ml, 56.0 mmol) andheating to 90° C. for 24 h, the title compound,N-{3-[5-(2-amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamidewas obtained (94 mg, 47% yield). ¹H NMR (400 MHz, DMSO-d6) δ ppm 10.83(s, 1H), 7.93 (d, J=5.2 Hz, 1H), 7.55-7.70 (m, 1H), 7.35-7.43 (m, 1H),7.31 (t, J=6.3 Hz, 1H), 7.14-7.27 (m, 3H), 6.70 (s, 2H), 5.79 (d, J=5.13Hz, 1H), 1.35 (s, 9H). MS (ESI): 519.9 [M+H]⁺.

Example 58bN-{3-[5-(2-Amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide

19.6 mg ofN-{3-[5-(2-Amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide(may be prepared in accordance with example 58a) was combined with 500μL of ethyl acetate in a 2-mL vial at room temperature. The slurry wastemperature-cycled between 0-40° C. for 48 hrs. The resulting slurry wasallowed to cool to room temperature and the solids were collected byvacuum filtration. The solids were analyzed by Raman, PXRD, DSC/TGAanalyses, which indicated a crystal form different from the crystal formresulting from Example 58a, above.

Example 58cN-{3-[5-(2-amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide

Step A: methyl 3-{[(2,6-difluorophenyl)sulfonyl]amino}-2-fluorobenzoate

Methyl 3-amino-2-fluorobenzoate (50 g, 1 eq) was charged to reactorfollowed by dichloromethane (250 mL, 5 vol). The contents were stirredand cooled to ˜15° C. and pyridine (26.2 mL, 1.1 eq) was added. Afteraddition of the pyridine, the reactor contents were adjusted to ˜15° C.and the addition of 2,6-difluororobenzenesulfonyl chloride (39.7 mL, 1.0eq) was started via addition funnel. The temperature during addition waskept <25° C. After complete addition, the reactor contents were warmedto 20-25° C. and held overnight. Ethyl acetate (150 mL) was added anddichloromethane was removed by distillation. Once distillation wascomplete, the reaction mixture was then diluted once more with ethylacetate (5 vol) and concentrated. The reaction mixture was diluted withethyl acetate (10 vol) and water (4 vol) and the contents heated to50-55° C. with stirring until all solids dissolve. The layers weresettled and separated. The organic layer was diluted with water (4 vol)and the contents heated to 50-55° for 20-30 min. The layers were settledand then separated and the ethyl acetate layer was evaporated underreduced pressure to ˜3 volumes. Ethyl Acetate (5 vol.) was added andagain evaporated under reduced pressure to ˜3 volumes. Cyclohexane (9vol) was then added to the reactor and the contents were heated toreflux for 30 min then cooled to 0° C. The solids were filtered andrinsed with cyclohexane (2×100 mL). The solids were air dried overnightto obtain methyl3-{[(2,6-difluorophenyl)sulfonyl]amino}-2-fluorobenzoate (94.1 g, 91%).

Step B:N-{3-[(2-chloro-4-pyrimidinyl)acetyl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide

Methyl 3-{[(2,6-difluorophenyl)sulfonyl]amino}-2-fluorobenzoate (490 g,1 equiv.), prepared generally in accordance with Step A, above, wasdissolved in THF (2.45 L, 5 vols) and stirred and cooled to 0-3° C. 1Mlithium bis(trimethylsilyl)amide in THF (5.25 L, 3.7 equiv.) solutionwas charged to the reaction mixture followed addition of2-chloro-4-methylpyrimidine (238 g, 1.3 equiv.) in THF (2.45 L, 5 vols).The reaction was then stirred for 1 hr. The reaction was quenched with4.5M HCl (3.92 L, 8 vols). The aqueous layer (bottom layer) was removedand discarded. The organic layer was concentrated under reduced pressureto ˜2 L. IPAC (isopropyl acetate) (2.45 L) was added to the reactionmixture which was then concentrated to ˜2 L. IPAC (0.5 L) and MTBE (2.45L) was added and stirred overnight under N₂. The solids were filtered.The solids and mother filtrate added back together and stirred forseveral hours. The solids were filtered and washed with MTBE (˜5 vol).The solids were placed in vacuum oven at 50° C. overnight. The solidswere dried in vacuum oven at 30° C. over weekend to obtainN-{3-[(2-chloro-4-pyrimidinyl)acetyl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide(479 g, 72%).

Step C:N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide

To a reactor vessel was chargedN-{3-[(2-chloro-4-pyrimidinyl)acetyl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide(30 g, 1 eq) followed by dichloromethane (300 mL). The reaction slurrywas cooled to ˜10° C. and N-bromosuccinimide (“NBS”) (12.09 g, 1 eq) wasadded in 3 approximately equal portions, stirring for 10-15 minutesbetween each addition. After the final addition of NBS, the reactionmixture was warmed to ˜20° C. and stirred for 45 min. Water (5 vol) wasthen added to the reaction vessel and the mixture was stirred and thenthe layers separated. Water (5 vol) was again added to thedichloromethane layer and the mixture was stirred and the layersseparated. The dichloromethane layers were concentrated to ˜120 mL.Ethyl acetate (7 vol) was added to the reaction mixture and concentratedto ˜120 mL. Dimethylacetamide (270 mL) was then added to the reactionmixture and cooled to ˜10° C. 2,2-Dimethylpropanethioamide (1.3 g, 0.5eq) in 2 equal portions was added to the reactor contents with stirringfor ˜5 minutes between additions. The reaction was warmed to 20-25° C.After 45 min, the vessel contents were heated to 75° C. and held for1.75 hours. The reaction mixture was then cooled to 5° C. and water (270ml) was slowly charged keeping the temperature below 30° C. Ethylacetate (4 vol) was then charged and the mixture was stirred and layersseparated. Ethyl acetate (7 vol) was again charged to the aqueous layerand the contents were stirred and separated. Ethyl acetate (7 vol) wascharged again to the aqueous layer and the contents were stirred andseparated. The organic layers were combined and washed with water (4vol) 4 times and stirred overnight at 20-25° C. The organic layers werethen concentrated under heat and vacuum to 120 mL. The vessel contentswere then heated to 50° C. and heptanes (120 mL) were added slowly.After addition of heptanes, the vessel contents were heated to refluxthen cooled to 0° C. and held for ˜2 hrs. The solids were filtered andrinsed with heptanes (2×2 vol). The solid product was then dried undervacuum at 30° C. to obtainN-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide(28.8 g, 80%).

Step D:N-{3-[5-(2-amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide

In 1 gal pressure reactor, a mixture ofN-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide(120 g) prepared in accordance with Step C, above, and ammoniumhydroxide (28-30%, 2.4 L, 20 vol) was heated in the sealed pressurereactor to 98-103° C. and stirred at this temperature for 2 hours. Thereaction was cooled slowly to room temperature (20° C.) and stirredovernight. The solids were filtered and washed with minimum amount ofthe mother liquor and dried under vacuum. The solids were added to amixture of EtOAc (15 vol)/water (2 vol) and heated to completedissolution at 60-70° C. and the aqueous layer was removed anddiscarded. The EtOAC layer was charged with water (1 vol) andneutralized with aq. HCl to ˜pH 5.4-5.5. and added water (1 vol). Theaqueous layer was removed and discarded at 60-70° C. The organic layerwas washed with water (1 vol) at 60-70° C. and the aqueous layer wasremoved and discarded. The organic layer was filtered at 60° C. andconcentrated to 3 volumes. EtOAc (6 vol) was charged into the mixtureand heated and stirred at 72° C. for 10 min, then cooled to 20° C. andstirred overnight. EtOAc was removed via vacuum distillation toconcentrate the reaction mixture to ˜3 volumes. The reaction mixture wasmaintained at ˜65-70° C. for ˜30 mins. Product crystals having the samecrystal form as those prepared in Example 58b (and preparable by theprocedure of Example 58b), above, in heptanes slurry were charged.Heptane (9 vol) was slowly added at 65-70° C. The slurry was stirred at65-70° C. for 2-3 hours and then cooled slowly to 0-5° C. The productwas filtered, washed with EtOAc/heptane (3/1 v/v, 4 vol) and dried at45° C. under vacuum to obtainN-{3-[5-(2-amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide(102.3 g, 88%).

Example 58dN-{3-[5-(2-amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamidemethanesulfonate

To a solution ofN-{3-[5-(2-amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide(204 mg, 0.393 mmol) in isopropanol (2 mL), methanesulfonic acid (0.131mL, 0.393 mmol) was added and the solution was allowed to stir at roomtemperature for 3 hours. A white precipitate formed and the slurry wasfiltered and rinsed with diethyl ether to give the title product as awhite crystalline solid (210 mg, 83% yield). ¹H NMR (400 MHz, DMSO-d6) δppm 10.85 (s, 1H) 7.92-8.05 (m, 1H) 7.56-7.72 (m, 1H) 6.91-7.50 (m, 7H)5.83-5.98 (m, 1H) 2.18-2.32 (m, 3H) 1.36 (s, 9H). MS (ESI): 520.0[M+H]⁺.

Example 58eN-{3-[5-(2-amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamidemethanesulfonate

N-{3-[5-(2-amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide(as may be prepared according to example 58a) (2.37 g, 4.56 mmol) wascombined with pre-filtered acetonitrile (5.25 vol, 12.4 mL). Apre-filtered solution of mesic acid (1.1 eq., 5.02 mmol, 0.48 g) in H₂O(0.75 eq., 1.78 mL) was added at 20° C. The temperature of the resultingmixture was raised to 50-60° C. while maintaining a low agitation speed.Once the mixture temperature reached to 50-60° C., a seed slurry ofN-{3-[5-(2-amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamidemethanesulfonate (1.0% w/w slurried in 0.2 vol of pre-filteredacetonitrile) was added, and the mixture was aged while agitating at aspeed fast enough to keep solids from settling at 50-60° C. for 2 hr.The mixture was then cooled to 0-5° C. at 0.25° C./min and held at 0-5°C. for at 6 hr. The mixture was filtered and the wet cake was washedtwice with pre-filtered acetonitrile. The first wash consisted of 14.2ml (6 vol) pre-filtered acetonitrile and the second wash consisted of9.5 ml (4 vol) pre-filtered acetonitrile. The wet solid was dried at 50°C. under vacuum, yielding 2.39 g (85.1% yield) of product.

Example 59N-{3-[5-(2-Amino-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide

Following a procedure analogous to the procedure described in Example51, Step B usingN-{3-[5-(2-chloro-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide(250 mg, 0.440 mmol) and ammonia in MeOH 7M (7 ml, 49.0 mmol) the titlecompound was obtained as a yellow solid (187 mg, 72% yield). ¹H NMR (400MHz, DMSO-d6) δ ppm 10.82 (br. s., 1H), 7.78 (d, J=5.3 Hz, 1H),7.55-7.71 (m, 1H), 7.31-7.43 (m, 1H), 7.10-7.30 (m, 4H), 6.52 (s, 2H),5.59 (d, J=5.2 Hz, 1H), 3.66 (t, J=4.3 Hz, 4H), 3.40 (d, J=4.5 Hz, 4H).MS (ESI): 549.1 [M+H]⁺.

Example 60N-{3-[5-(2-Amino-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide

Following a procedure analogous to the procedure described in Example51, Step B usingN-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide(200 mg, 0.381 mmol) and ammonia in MeOH 7M (6 ml, 42.0 mmol) andheating to 45° C. overnight, the title compound was obtained as a lightyellow solid (128 mg, 63% yield). ¹H NMR (400 MHz, DMSO-d6) δ ppm 10.84(s, 1H), 7.93 (d, J=5.2 Hz, 1H), 7.55-7.70 (m, 1H), 7.34-7.43 (m, 1H),7.30 (t, J=6.3 Hz, 1H), 7.13-7.27 (m, 3H), 6.71 (s, 2H), 5.79 (d, J=5.1Hz, 1H), 3.17-3.27 (m, 1H), 1.30 (d, J=6.9 Hz, 6H). MS (ESI): 506.1[M+H]⁺.

Example 61N-{3-[5-(2-Amino-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-3-pyridinesulfonamide

Step A:N-{3-[5-(2-Chloro-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-3-pyridinesulfonamide

To a solution of3-(5-(2-chloropyrimidin-4-yl)-2-morpholinothiazol-4-yl)-2-fluoroaniline(3 g, 7.7 mmol) in pyridine (15 mL) was added pyridine-3-sulfonylchloride (1.49 g, 8.4 mmol) dropwise to the mixture. The reaction wasstirred at rt overnight. The reaction was washed with water (100 mL),and extracted with DCM (2×100 mL). The organic layer was washed withbrine, dried over anhydrous Na₂SO₄, filtered and concentrated underreduced pressure to give the crude product, which was purified by columnchromatography on silica gel (petroleum ether:EtOAc 5:1) to afford thetitle compound of Step A (2.9 g, 71.5% yield). ¹H NMR (400 MHz, DMSO-d6)δ ppm 10.55-10.60 (br, 1H), 8.82-8.86 (m, 1H), 8.72-8.76 (m, 1H), 8.30(d, J=5.3 Hz, 1H), 8.07-8.13 (m, 1H), 7.51-7.52 (m, 1H), 7.39-7.47 (m,1H), 7.27-7.40 (m, 2H), 6.47 (d, J=5.3 Hz, 1H) 3.47-3.57 (m, 4H),3.67-3.75 (m, 4H). MS (ES+): 533 [M+H]⁺.

Step B:N-{3-[5-(2-Amino-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-3-pyridinesulfonamide

A suspension ofN-{3-[5-(2-chloro-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-3-pyridinesulfonamide(195 mg, 0.366 mmol) and ammonia in i-PrOH 2M (8 mL, 16.0 mmol) washeated in a sealed tube at 100° C. overnight. The reaction mixture wasevaporated onto silica gel and chromatographed (10-100% 1:9 MeOH:EtOAcin DCM). The title compound was obtained as a yellow solid aftertrituration in diethyl ether (88 mg, 45% yield). ¹H NMR (400 MHz,DMSO-d6) δ ppm 10.56 (s, 1H), 8.84 (d, J=1.7 Hz, 1H), 8.75 (dd, J=4.7,1.0 Hz, 1H), 7.99-8.15 (m, 1H), 7.82 (d, J=5.3 Hz, 1H), 7.55 (dd, J=7.9,5.0 Hz, 1H), 7.33-7.46 (m, 1H), 7.24 (d, J=6.3 Hz, 2H), 6.55 (br. s.,2H), 5.56 (d, J=5.2 Hz, 1H), 3.59-3.72 (m, 4H), 3.34-3.49 (m, 4H). MS(ESI): 514.1 [M+H]⁺.

Example 62N-{3-[5-(2-Amino-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2-furansulfonamide

Step A:N-{3-[5-(2-Chloro-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2-furansulfonamide

To a solution of3-(5-(2-chloropyrimidin-4-yl)-2-morpholinothiazol-4-yl)-2-fluoroaniline(3 g, 7.6 mmol) in DCM (50 mL) was added pyridine (10 mL). The mixturewas cooled to 0° C. Furan-2-sulfonyl chloride (1.4 g, 8.4 mmol) in DCM(5 mL) was added dropwise to the mixture. The reaction was stirred at rtovernight. Then the reaction was washed with water (100 mL), andextracted with DCM (2×100 mL). The organic layer was washed with brine,dried over anhydrous Na₂SO₄, filtrated and concentrated under reducedpressure to give the crude product, which was purified by columnchromatography on silica gel (petroleum ether:EtOAc 4:1) to afford thetitle compound of Step A (2.5 g, 63% yield). ¹H NMR (400 MHz, DMSO-d6) δppm 8.07 (d, J=5.5 Hz, 1H), 7.59-7.66 (m, 1H), 7.42-7.75 (br, 1H),7.13-7.20 (m, 2H), 7.02 (d, J=5.5 Hz, 1H), 6.93-6.98 (m, 1H), 6.37-6.42(m, 2H), 3.50-3.57 (m, 4H), 3.72-3.78 (m, 4H). MS (ES+): 522 [M+H]⁺.

Step B:N-{3-[5-(2-Amino-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2-furansulfonamide

A suspension ofN-{3-[5-(2-chloro-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2-furansulfonamide(150 mg, 0.287 mmol) and NH₄OH (5 mL, 128 mmol) was heated in amicrowave reactor at 120° C. for 40 min. LC-MS looks good for desiredproduct. The reaction mixture was neutralized with 5N HCl and extractedwith DCM×2. The crude mixture was evaporated onto silica gel andchromatographed (10-50% 1:9 MeOH:EtOAc in DCM). The title compound wasobtained as a yellow solid after trituration in MeOH (102 mg, 68%yield). ¹H NMR (400 MHz, DMSO-d6) δ ppm 10.57 (s, 1H), 7.78-7.94 (m,2H), 7.34 (td, J=7.4, 2.0 Hz, 1H), 7.14-7.30 (m, 2H), 7.03 (d, J=3.5 Hz,1H), 6.44-6.61 (m, 3H), 5.64 (d, J=5.3 Hz, 1H), 3.67 (t, J=4.7 Hz, 4H),3.41 (t, J=4.6 Hz, 4H). MS (ESI): 502.2 [M−H]⁻.

Example 63N-{3-[5-(2-Amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}cyclohexanesulfonamide

Step A: 2-Propen-1-yl{3-[5-(2-amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}carbamate

A solution of 2-propen-1-yl{3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}carbamate(535 mg, 1.197 mmol) and ammonia in MeOH 7N (6 ml, 42.0 mmol) was heatedto 80° C. for 24 h. The crude reaction mixture was evaporated ontosilica gel and chromatographed, (0-15% MeOH in DCM). The title compoundwas obtained as a yellow foam (233 mg, 41% yield). MS (ESI): 428.1[M+H]⁺.

Step B:4-[4-(3-Amino-2-fluorophenyl)-2-(1,1-dimethylethyl)-1,3-thiazol-5-yl]-2-pyrimidinamine

A solution of 2-propen-1-yl{3-[5-(2-amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}carbamate(220 mg, 0.515 mmol) in TBAF (1 mL, 1.0 mmol) in 1M THF was heated in amicrowave reactor at 130° C. for 10 min. The crude reaction mixture wasevaporated onto silica gel and chromatographed (1:9:90 NH₄OH:MeOH:DCM inDCM 10-80%). The title compound was obtained as a white solid (100 mg,56% yield). MS (ESI): 344.1 [M+H]⁺.

Step C:N-{3-[5-(2-Amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}cyclohexanesulfonamide

To a solution of4-[4-(3-amino-2-fluorophenyl)-2-(1,1-dimethylethyl)-1,3-thiazol-5-yl]-2-pyrimidinamine(100 mg, 0.291 mmol) in DCM (2 ml), pyridine (0.4 mL, 4.95 mmol) wasadded followed by cyclohexylsulfonyl chloride (0.042 mL, 0.291 mmol).The solution was allowed to stir at rt for 24 h at rt. The solvent wasremoved and the concentrated residue was allowed to sit at rt overnight.The residue was then evaporated onto silica gel and chromatographed (1:9MeOH:EtOAc in DCM). The title compound was obtained after trituration indiethyl ether (50 mg, 33% yield). ¹H NMR (400 MHz, DMSO-d6) δ ppm 9.65(s, 1H), 8.02 (d, J=5.1 Hz, 1H), 7.52 (t, J=7.7 Hz, 1H), 7.33 (t, J=6.4Hz, 1H), 7.26 (t, J=7.9 Hz, 1H), 6.72 (s, 2H), 6.01 (d, J=5.1 Hz, 1H),2.79-2.92 (m, 1H), 1.92-2.05 (m, 2H), 1.68 (d, J=12.6 Hz, 2H), 1.47-1.57(m, 1H), 1.38 (s, 9H), 1.22-1.36 (m, 2H), 1.07-1.24 (m, 3H). MS (ESI):490.2 [M+H]⁺.

Example 64N-{3-[5-(2-Amino-4-pyrimidinyl)-2-(tetrahydro-2H-pyran-4-yl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide

A suspension ofN-{3-[5-(2-chloro-4-pyrimidinyl)-2-(tetrahydro-2H-pyran-4-yl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide(20.7 g, 36.5 mmol) and ammonia hydroxide (500 mL) was heated in a steelreactor to 100° C. After 3 h, the reaction cooled and checked by HPLC.The reaction mixture was concentrated. The reaction mixture wad dilutedwith CH₂Cl₂ (300 mL) and water (300 mL) then acidified with 6N HCl topH=1. The mixture was extracted with 1% MeOH in CH₂Cl₂ (4×). The CH₂Cl₂layer were dried over Na₂SO₄ and filtered and concentrated to 400 mL.Ethanol (400 mL) was added to the reaction mixture and concentrated todryness. Ethanol (400 mL) was added again to the reaction mixture andconcentrated to dryness. Ethanol (500 mL) was added to the reactionmixture and refluxed. After 4 h, the reaction mixture was cooled to 0°C., filtered, and wash with EtOH. The product was dried under vacuum at60° C. for 2 days. Title compound was obtained as an off-white solid (17g, 85% yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.90 (br. s., 1H), 7.98(d, J=5.3 Hz, 1H), 7.56-7.84 (m, 1H), 6.93-7.54 (m, 5H), 6.77 (br. s.,2H), 5.85 (d, J=4.6 Hz, 1H), 3.92 (d, J=9.9 Hz, 2H), 3.46 (t, J=11.2 Hz,2H), 3.20-3.32 (m, 1H), 1.90-2.06 (m, 2H), 1.57-1.81 (m, 2H). MS (ESI):548.10 [M+H]⁺.

Example 65N-{3-[2-(1,1-Dimethylethyl)-5-(2-methyl-4-pyrimidinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide

To a suspension ofN-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide(200 mg, 0.371 mmol) and tetrakis(triphenylphoshine)palladium (8.6 mg,7.4 μmol) in THF (5 mL) was added a 2 M solution of methylzinc chloridein THF (0.371 mL, 0.742 mmol). The suspension was stirred for 16 h at60° C. The reaction mixture was partitioned between water and EtOAc, andthe aqueous layer was extracted with EtOAc. The combined organic layerswere dried over anhydrous Na₂SO₄, filtered, concentrated, and purifiedvia column chromatography, eluting with 0-100% EtOAc/DCM. The desiredfractions were combined and concentrated to generate 90 mg (0.174 mmol,46.8% yield) of the title compound as a white powder. ¹H NMR (400 MHz,DMSO-d₆): δ 10.75 (s, 1H), 8.47 (d, J=5.3 Hz, 1H), 7.52-7.58 (m, 1H),7.40-7.50 (m, 4H), 7.29 (t, J=7.8 Hz, 1H), 6.64 (d, J=5.3 Hz, 1H), 2.58(s, 3H), 1.42 (s, 9H). MS (ESI): 520.0 [M+H]⁺.

Example 65 (Alternative)N-{3-[2-(1,1-Dimethylethyl)-5-(2-methyl-4-pyrimidinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide

To a suspension ofN-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide(21.54 g, 40 mmol) in 1,4-dioxane (300 mL) was bubble with argon for 10min. The reaction mixture was treated with 2N dimethylzinc in toluene(40 mL, 80 mmol) under argon. The reaction mixture was treated withPdCl₂(dppf).CH₂Cl₂ adduct (0.326 g, 0.400 mmol) and heated to 80° C.After 2 h, the reaction was check by HPLC. The reaction was cooled toroom temperature and slowly added MeOH until reaction was quenched.After quenched, the reaction mixture was diluted with NaHCO₃ (sat'd)(200 mL) and extracted with EtOAc (3×, 200 mL). The EtOAc layers werestirred with activated carbon (darco G-60, 100 mesh, powder) for 1 h.The reaction mixture was filtered through pad of SiO2 (3″×3″) and washedwith EtOAc. The reaction mixture was concentrated. IPA (350 mL) was tothe reaction mixture and heated to reflux. After 2 h, the reactionmixture was cooled to room temperature and filtered and washed with IPAand water (200 mL). The product was dried under vacuum at 60° C. for 2days. Title compound was obtained as an off-white solid (17.5 g, 80%yield). ¹H NMR (400 MHz, DMSO-d₆): δ 10.75 (s, 1H), 8.47 (d, J=5.3 Hz,1H), 7.52-7.58 (m, 1H), 7.40-7.50 (m, 4H), 7.29 (t, J=7.8 Hz, 1H), 6.64(d, J=5.3 Hz, 1H), 2.58 (s, 3H), 1.42 (s, 9H). MS (ESI): 519 [M+H]⁺.

Example 66N-{3-[2-(1,1-Dimethylethyl)-5-(4-pyrimidinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide

To a solution ofN-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide(100 mg, 0.186 mmol) and TEA (52 μL, 0.371 mmol) in EtOH (5 mL) and MeOH(1 mL) was added 10% (w/w) palladium on carbon (50 mg, 0.048 mmol). Thesuspension was transferred to a hydrogenation bottle, and installed in aFisher-Porter hydrogenation apparatus. The bottle was charged with H₂(50 psi) and stirred at rt for 72 h. The reaction mixture was filteredthrough Celite and concentrated to generate 90 mg (0.178 mmol, 96%) ofthe title compound as a white powder. ¹H NMR (400 MHz, DMSO-d₆): δ 10.75(s, 1H), 9.10 (s, 1H), 8.60 (d, J=5.3 Hz, 1H), 7.53-7.57 (m, 1H),7.40-7.50 (m, 4H), 7.30 (t, J=7.6 Hz, 1H), 6.89 (d, J=5.3 Hz, 1H), 1.43(s, 9H). MS (ESI): 504.6 [M+H]+.

Example 672,5-Difluoro-N-{2-fluoro-3-[5-{2-[(2-methylpropyl)amino]-4-pyrimidinyl}-2-(tetrahydro-2H-pyran-4-yl)-1,3-thiazol-4-yl]phenyl}benzenesulfonamide

Following a procedure analogous to the procedure described in Example18, Step B usingN-{3-[5-(2-chloro-4-pyrimidinyl)-2-(tetrahydro-2H-pyran-4-yl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide(0.150 g, 0.265 mmol) and isobutylamine (1.052 mL, 10.58 mmol) the titlecompound was obtained as an off-white solid (108 mg, 0.166 mmol, 62.9%yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.77 (s, 1H), 8.02 (d, J=5.1Hz, 1H), 7.44-7.64 (m, 3H), 7.31-7.44 (m, 3H), 7.27 (t, J=7.8 Hz, 1H),5.68-6.07 (m, 1H), 3.83-3.96 (m, 2H), 3.38-3.55 (m, 2H), 3.21-3.32 (m,1H), 2.87-3.18 (m, 2H), 1.92-2.06 (m, 2H), 1.61-1.92 (m, 3H), 0.74-0.99(m, 6H). MS (ESI): 604.20 [M+H]⁺.

Example 68N-{5-[5-(2-Amino-4-pyrimidinyl)-2-(tetrahydro-2H-pyran-4-yl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide

Following a procedure analogous to the procedure described in Example51, Step B usingN-{5-[5-(2-chloro-4-pyrimidinyl)-2-(tetrahydro-2H-pyran-4-yl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide(0.120 g, 0.212 mmol) and ammonia (7N solution in MeOH, 4.54 mL, 31.7mmol) the title compound was obtained as a white solid (71 mg, 0.13mmol, 60% yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.80 (s, 1H), 8.06(d, J=5.1 Hz, 1H), 7.45-7.71 (m, 3H), 7.34-7.45 (m, 2H), 7.23-7.34 (m,1H), 6.80 (s, 2H), 6.19 (d, J=5.1 Hz, 1H), 3.88-4.03 (m, 2H), 3.40-3.56(m, 2H), 3.21-3.31 (m, 1H), 1.92-2.07 (m, 2H), 1.63-1.82 (m, 2H). MS(ESI): 548.11 [M+H]⁺.

Example 692,5-Difluoro-N-{2-fluoro-5-[5-{2-[(2-methylpropyl)amino]-4-pyrimidinyl}-2-(tetrahydro-2H-pyran-4-yl)-1,3-thiazol-4-yl]phenyl}benzenesulfonamide

Following a procedure analogous to the procedure described in Example18, Step B usingN-{5-[5-(2-chloro-4-pyrimidinyl)-2-(tetrahydro-2H-pyran-4-yl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide(120 mg, 0.212 mmol) and isobutylamine (1.1 mL, 11 mmol) the titlecompound was obtained as a light orange solid (94 mg, 0.16 mmol, 74%yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.81 (br. s., 1H), 7.83-8.30(m, 1H), 7.43-7.71 (m, 3H), 7.30-7.43 (m, 3H), 7.15-7.30 (m, 1H),5.97-6.36 (m, 1H), 3.73-4.07 (m, 2H), 3.47 (t, J=11.0 Hz, 2H), 3.20-3.31(m, 1H), 2.94-3.16 (m, 2H), 1.93-2.08 (m, 2H), 1.61-1.89 (m, 3H),0.75-0.93 (m, 6H). MS (ESI): 604.19 [M+H]⁺.

Example 702,5-Difluoro-N-{2-fluoro-5-[5-(2-{[1-(methylsulfonyl)-4-piperidinyl]amino}-4-pyrimidinyl)-2-(tetrahydro-2H-pyran-4-yl)-1,3-thiazol-4-yl]phenyl}benzenesulfonamide

Following a procedure analogous to the procedure described in Example 1usingN-{5-[5-(2-chloro-4-pyrimidinyl)-2-(tetrahydro-2H-pyran-4-yl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide(120 mg, 0.212 mmol) and 1-(methylsulfonyl)-4-piperidinamine (377 mg,2.12 mmol) in THF (1 mL) the title compound was obtained as a lightyellow solid (89 mg, 0.12 mmol, 59% yield). ¹H NMR (400 MHz, DMSO-d₆) δppm 10.83 (s, 1H), 8.14 (d, J=4.9 Hz, 1H), 7.46-7.73 (m, 3H), 7.34-7.45(m, 3H), 7.22-7.34 (m, 1H), 5.99-6.51 (m, 1H), 3.95 (dd, J=11.4, 2.0 Hz,2H), 3.41-3.58 (m, 4H), 3.18-3.33 (m, 1H), 2.69-2.93 (m, 5H), 1.81-2.06(m, 5H), 1.66-1.81 (m, 2H), 1.42-1.65 (m, 2H). MS (ESI): 709.18 [M+H]⁺.

Example 71N-{3-[5-(2-Amino-4-pyrimidinyl)-2-(tetrahydro-3-furanyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide

Step A: Methyl tetrahydro-3-furancarboxylate

To a solution of tetrahydro-3-furancarboxylic acid (10.00 g, 86.0 mmol)in MeOH (172 mL) was added sulfuric acid (13.8 mL, 258 mmol). Thereaction was heated to reflux for 18 h. The reaction was then cooled tort and concentrated. The residue was partitioned between water (500 mL)and DCM (200 mL). The phases were separated and the aqueous fraction wasextracted with DCM (200 mL). The combined organic fractions were washedwith saturated aqueous NaHCO₃ (200 mL) and brine (200 mL), dried overNa₂SO₄, filtered, and concentrated to afford methyltetrahydro-3-furancarboxylate (10.1 g, 78 mmol, 90% yield) as a paleyellow oil. ¹H NMR (400 MHz, CDCl₃) δ ppm 3.99 (t, J=8.4 Hz, 1H),3.86-3.95 (m, 2H), 3.76-3.86 (m, 1H), 3.71 (s, 3H), 3.01-3.18 (m, 1H),2.03-2.32 (m, 2H).

Step B: Tetrahydro-3-furancarboxamide

A solution of methyl tetrahydro-3-furancarboxylate (10.1 g, 78 mmol) inammonia (7N solution in MeOH, 55.5 mL, 388 mmol) was heated to 80° C.for 72 h. The reaction mixture was then concentrated and dried for 16 hunder high vacuum to afford tetrahydro-3-furancarboxamide (7.73 g, 67.1mmol, 86% yield) as an off-white solid. ¹H NMR (400 MHz, CDCl₃) δ ppm5.12-6.10 (m, 2H), 3.86-4.05 (m, 3H), 3.74-3.86 (m, 1H), 2.84-3.04 (m,J=7.1, 6.8, 6.6, 6.6 Hz, 1H), 2.00-2.31 (m, 2H).

Step C: Tetrahydro-3-furancarbothioamide

A solution of tetrahydro-3-furancarboxamide (7.73 g, 67.1 mmol) andLawesson's reagent (13.6 g, 33.6 mmol) in THF (90 mL) was heated toreflux for 16 h. The reaction was cooled to rt, poured into saturatedaqueous NaHCO₃ (250 mL) and extracted with diethyl ether (4×100 mL). Thecombined organic extracts were dried over Na₂SO₄, filtered, andconcentrated. Purification by chromatography (20 to 100% EtOAc:hexanes)afforded tetrahydro-3-furancarbothioamide (3.78 g, 28.8 mmol, 42.9%yield) as a white solid. ¹H NMR (400 MHz, CDCl₃) δ ppm 7.35 (br. s.,2H), 3.95-4.30 (m, 2H), 3.70-3.94 (m, 2H), 3.40-3.69 (m, 1H), 2.28-2.52(m, 1H), 2.14-2.28 (m, 1H).

Step D:N-{3-[5-(2-Chloro-4-pyrimidinyl)-2-(tetrahydro-3-furanyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide

Following a procedure analogous to the procedure described in Example18, Step A usingN-{3-[(2-chloro-4-pyrimidinyl)acetyl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide(1.00 g, 2.26 mmol), NBS (0.423 g, 2.38 mmol) andtetrahydro-3-furancarbothioamide (0.386 g, 2.94 mmol) the title compoundof Step D was obtained as an orange solid (890 mg, 1.42 mmol, 62.6%yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.94 (s, 1H), 8.56 (d, J=5.5Hz, 1H), 7.59-7.83 (m, 1H), 7.40-7.55 (m, 2H), 7.33 (t, J=7.8 Hz, 1H),7.24 (t, J=9.1 Hz, 2H), 6.87 (d, J=5.3 Hz, 1H), 3.98-4.09 (m, 1H),3.71-3.99 (m, 4H), 2.35-2.48 (m, 1H), 2.09-2.28 (m, 1H). MS (ESI) 553.03[M+H]⁺.

Step E:N-{3-[5-(2-Amino-4-pyrimidinyl)-2-(tetrahydro-3-furanyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide

Following a procedure analogous to the procedure described in Example51, Step B usingN-{3-[5-(2-chloro-4-pyrimidinyl)-2-(tetrahydro-3-furanyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide(0.100 g, 0.181 mmol) and ammonia (7N solution in MeOH, 3.88 mL, 27.1mmol) the title compound was obtained as a light yellow solid (53 mg,0.099 mmol, 55% yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.90 (s, 1H),7.99 (d, J=5.1 Hz, 1H), 7.62-7.79 (m, 1H), 7.40-7.49 (m, 1H), 7.36 (t,J=6.1 Hz, 1H), 7.17-7.33 (m, 3H), 6.78 (br. s., 2H), 5.84 (d, J=5.1 Hz,1H), 3.96-4.09 (m, 1H), 3.73-3.95 (m, 4H), 2.34-2.47 (m, 1H), 2.05-2.22(m, 1H). MS (ESI) 534.10 [M+H]⁺.

Example 72N-{3-[5-(2-Amino-4-pyrimidinyl)-2-cyclobutyl-1,3-thiazol-4-yl]-2-chlorophenyl}-2,6-difluorobenzenesulfonamide

Step A:N-{2-Chloro-3-[5-(2-chloro-4-pyrimidinyl)-2-cyclobutyl-1,3-thiazol-4-yl]phenyl}-2,6-difluorobenzenesulfonamide

Following a procedure analogous to the procedure described in Example18, Step A usingN-{2-chloro-3-[(E)-2-(2-chloro-4-pyrimidinyl)-1-hydroxyethenyl]phenyl}-2,6-difluorobenzenesulfonamide(1.2 g, 2.5 mmol), NBS (0.45 g, 2.5 mmol) and cyclobutanecarbothioamide(0.29 g, 2.5 mmol) the title compound was obtained as a white solid(0.75 g, 1.6 mmol, 54% yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm10.92-10.69 (m, 1H), 8.32-8.85 (m, 1H), 7.83-7.57 (m, 1H), 7.59-7.31 (m,3H), 7.33-7.07 (m, 2H), 6.49 (d, J=5.3 Hz, 1H), 3.89 (quin, J=8.5 Hz,1H), 2.67-2.14 (m, 4H), 2.14-1.79 (m, 2H). MS (ESI): 553 [M+H]⁺.

Step B:N-{3-[5-(2-Amino-4-pyrimidinyl)-2-cyclobutyl-1,3-thiazol-4-yl]-2-chlorophenyl}-2,6-difluorobenzenesulfonamide

Following a procedure analogous to the procedure described in Example51, Step B usingN-{2-chloro-3-[5-(2-chloro-4-pyrimidinyl)-2-cyclobutyl-1,3-thiazol-4-yl]phenyl}-2,6-difluorobenzenesulfonamide(0.20 g, 0.36 mmol) and 7N ammonia in MeOH (10 ml, 70 mmol) the titlecompound was obtained (0.030 g, 0.056 mmol, 15%). ¹H NMR (400 MHz,DMSO-d₆) δ ppm 10.80 (s, 1H), 7.95 (d, J=5.1 Hz, 1H), 7.64 (dd, J=14.3,2.0 Hz, 1H), 7.55-7.38 (m, 2H), 7.34 (d, J=7.0 Hz, 1H), 7.18 (t, J=9.1Hz, 2H), 6.72 (br, 2H), 5.61 (d, J=5.1 Hz, 1H), 3.83 (quin, J=8.4 Hz,1H), 3.45-3.19 (m, 1H), 2.38 (q, J=8.5 Hz, 1H), 2.24 (quin, J=9.1 Hz,1H), 2.10-1.92 (m, 1H), 1.86 (q, J=9.4 Hz, 1H), 1.06 (t, J=7.0 Hz, 1H).MS (ESI): 534 [M+H]⁺.

Example 732,5-Difluoro-N-{2-fluoro-5-[5-[2-(methylamino)-4-pyrimidinyl]-2-(1-methylethyl)-1,3-thiazol-4-yl]phenyl}benzenesulfonamide

Following a procedure analogous to the procedure described in Example 1usingN-{5-[5-(2-chloro-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide(0.10 g, 0.190 mmol) and methylamine in THF (1.0 mL, 2.0 mmol) the titlecompound was obtained (0.082 g, 0.16 mmol, 83% yield). ¹H NMR (400 MHz,DMSO-d₆) δ 10.75 (1H, s), 8.08-8.00 (m, 1H), 7.59-7.40 (m, 3H),7.39-7.30 (m, 2H), 7.27-7.11 (m, 2H), 6.16 (br. s., 1H), 3.30-3.21 (m,1H), 2.71 (br, 3H), 1.31 (d, J=7.0 Hz, 6H). MS (ESI): 520 [M+H]⁺.

Example 742,5-Difluoro-N-[2-fluoro-5-(2-(1-methylethyl)-5-{2-[(2,2,6,6-tetramethyl-4-piperidinyl)amino]-4-pyrimidinyl}-1,3-thiazol-4-yl)phenyl]benzenesulfonamide

Following a procedure analogous to the procedure described in Example 1usingN-{5-[5-(2-chloro-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide(0.10 g, 0.19 mmol) and 2,2,6,6-tetramethyl-4-piperidinamine (0.30 g,1.9 mmol) the title compound was obtained (0.035 g, 0.054 mmol, 29%yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.88 (s, 1H), 8.95-8.72 (m,1H), 8.20 (d, J=4.9 Hz, 1H), 7.95-7.72 (m, 1H), 7.72-7.20 (m, 6H),6.43-6.20 (m, 1H), 2.05 (d, J=12.8 Hz, 2H), 1.75-1.27 (m, 22H). MS(ESI): 645 [M+H]⁺.

Example 752,5-Difluoro-N-{2-fluoro-5-[2-(1-methylethyl)-5-(2-{[1-(methylsulfonyl)-4-piperidinyl]amino}-4-pyrimidinyl)-1,3-thiazol-4-yl]phenyl}benzenesulfonamide

Following a procedure analogous to the procedure described in Example 1usingN-{5-[5-(2-chloro-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide(0.30 g, 0.57 mmol), 1-(methylsulfonyl)-4-piperidinamine (0.3 g, 1.7mmol) and THF (1 mL) the title compound was obtained (0.32 g, 0.48 mmol,84% yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.82 (s, 1H), 8.13 (d,J=5.0 Hz, 1H), 7.71-7.44 (m, 3H), 7.45-7.32 (m, 3H), 7.29 (t, J=9.2 Hz,1H), 6.30 (m, 1H), 3.50 (m, 2H), 3.30-3.24 (m, 1H), 2.86 (s, 3H),2.83-2.64 (m, 2H), 1.90 (m, 2H), 1.67-1.44 (m, 2H), 1.36 (d, J=6.8 Hz,6H). MS (ESI): 667 [M+H]⁺.

Example 762,5-Difluoro-N-(2-fluoro-5-{2-(1-methylethyl)-5-[2-(tetrahydro-2H-pyran-4-ylamino)-4-pyrimidinyl}-1,3-thiazol-4-yl]phenyl)benzenesulfonamide

Following a procedure analogous to the procedure described in Example 1usingN-{5-[5-(2-chloro-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide(0.10 g, 0.19 mmol) and tetrahydro-2H-pyran-4-amine (0.19 g, 1.90 mmol)in THF (1 mL) the title compound was obtained as an off-white solid(0.094 g, 0.16 mmol, 84% yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.02(d, J=5.2 Hz, 1H), 7.75-7.65 (m, 1H), 7.55-7.38 (m, 1H), 7.38-7.28 (m,1H), 7.28-7.11 (m, 3H), 7.11-6.88 (m, 2H), 6.22 (d, J=5.2 Hz, 1H), 5.06(d, J=7.8 Hz, 1H), 4.02-3.92 (m, 4H), 3.56-3.46 (m, 2H), 3.29 (quin,J=6.9 Hz, 1H), 2.00 (d, J=13.2 Hz, 2H), 1.41 (d, J=7.0 Hz, 6H). MS(ESI): 590 [M+H]⁺.

Example 77N-{5-[5-{2-[(1-Acetyl-4-piperidinyl)amino]-4-pyrimidinyl}-2-(1-methylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide

Following a procedure analogous to the procedure described in Example 1usingN-{5-[5-(2-chloro-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide(0.10 g, 0.19 mmol) and 1-acetyl-4-piperidinamine (0.27 g, 1.9 mmol) inTHF (1 mL) the title compound was obtained as an off-white solid (0.075g, 0.12 mmol, 62% yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.82 (s, 1H),8.12 (d, J=5.0 Hz, 1H), 7.68-7.43 (m, 3H), 7.44-7.17 (m, 5H), 4.33-4.18(m, 1H), 3.83-3.73 (m, 1H), 3.44-3.20 (m, 2H), 2.66-2.32 (m, 4H), 1.99(s, 3H), 1.36 (d, J=6.8 Hz, 6H), 1.35-1.10 (m, 2H). MS (ESI): 631[M+H]⁺.

Example 78N-{3-[2-(1,1-Dimethylethyl)-5-(2-{[1-(methylsulfonyl)-4-piperidinyl]amino}-4-pyrimidinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide

Following a procedure analogous to the procedure described in Example 1usingN-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide(0.10 g, 0.19 mmol) and 1-(methylsulfonyl)-4-piperidinamine (0.30 g, 1.7mmol) in 2,2,2-trifluoroethanol (2 mL) the title compound was obtained(0.026 g, 0.038 mmol, 20% yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.84(s, 1H), 8.03 (br. s., 1H), 7.72-7.54 (m, 1H), 7.47-7.06 (m, 7H),3.53-3.38 (m, 2H), 2.83 (s, 3H), 2.83-2.72 (m, 3H), 1.91-1.73 (m, 2H),1.58-1.32 (m, 2H), 1.36 (s, 9H). MS (ESI): 681 [M+H]⁺.

Example 792,6-Difluoro-N-{2-fluoro-3-[5-(2-{[1-(methylsulfonyl)-4-piperidinyl]amino}-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]phenyl}benzenesulfonamide

Following a procedure analogous to the procedure described in Example 1usingN-{3-[5-(2-chloro-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide(0.107 g, 0.188 mmol) and 1-(methylsulfonyl)-4-piperidinamine (0.3 g,1.68 mmol) in 2,2,2-trifluoroethanol (2 mL) the title compound wasobtained (0.020 g, 0.028 mmol, 15% yield). ¹H NMR (400 MHz, DMSO-d₆) δppm 10.83 (s, 1H), 7.85 (d, J=5.1 Hz, 2H), 7.70-7.57 (m, 2H), 7.42-7.33(m, 2H), 7.30-7.03 (m, 4H), 5.47-5.86 (m, 1H) 3.72-3.31 (m, 11H),2.91-2.73 (m, 5H), 1.92-1.77 (m, 2H), 1.58-1.40 (m, 2H). MS (ESI): 710[M+H]⁺.

Example 80N-{5-[2-Cyclobutyl-5-(2-{[1-(methylsulfonyl)-4-piperidinyl]amino}-4-pyrimidinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide

Step A:N-{5-[5-(2-Chloro-4-pyrimidinyl)-2-cyclobutyl-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide

Following a procedure analogous to the procedure described in Example18, Step A usingN-{5-[(2-chloro-4-pyrimidinyl)acetyl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide(1.34 g, 3.03 mmol), NBS (0.540 g, 3.03 mmol), cyclobutanecarbothioamide(0.349 g, 3.03 mmol) the title compound of Step A was obtained (0.5 g,0.931 mmol, 30.7% yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.74 (s, 1H),8.52 (d, J=5.3 Hz, 1H), 7.58-7.33 (m, 6H), 7.28 (t, J=7.9 Hz, 1H), 6.83(d, J=5.3 Hz, 1H), 3.89 (quin, J=8.6 Hz, 1H), 2.43-2.19 (m, 4H),2.08-1.92 (m, 1H), 1.92-1.78 (m, 1H). MS (ESI): 537 [M+H]⁺.

Step B:N-{5-[2-Cyclobutyl-5-(2-{[1-(methylsulfonyl)-4-piperidinyl]amino}-4-pyrimidinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide

Following a procedure analogous to the procedure described in Example 1usingN-{5-[5-(2-chloro-4-pyrimidinyl)-2-cyclobutyl-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide(0.10 g, 0.19 mmol) was added 1-(methylsulfonyl)-4-piperidinamine (0.33g, 1.9 mmol) and THF (2 mL) the title compound was obtained (0.12 g,0.18 mmol, 98% yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.77 (s, 1H),8.08 (d, J=5.1 Hz, 1H), 7.64-7.19 (m, 7H), 6.34-6.01 (m, 1H), 3.83(quin, J=8.5 Hz, 1H), 3.72-3.40 (m, 2H), 2.91-2.64 (m, 5H), 2.43-2.15(m, 6H), 2.08-1.77 (m, 3H), 1.63-1.33 (m, 2H). MS (ESI): 679 [M+H]⁺.

Example 81N-{3-[2-Cyclobutyl-5-(2-{[1-(methylsulfonyl)-4-piperidinyl]amino}-4-pyrimidinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide

Step A:N-{3-[5-(2-Chloro-4-pyrimidinyl)-2-cyclobutyl-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide

Following a procedure analogous to the procedure described in Example18, Step A usingN-(3-(2-(2-chloropyrimidin-4-yl)acetyl)-2-fluorophenyl)-2,5-difluorobenzenesulfonamide(1.1 g, 2.5 mmol), NBS (0.44 g, 2.5 mmol) cyclobutanecarbothioamide(0.29 g, 2.5 mmol) the title compound of Step A was obtained (0.30 g,0.56 mmol, 22% yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.80 (s, 1H),8.52 (d, J=5.3 Hz, 1H), 7.63-7.22 (m, 6H), 7.07 (d, J=5.3 Hz, 1H), 3.89(quin, J=8.5 Hz, 1H), 2.44-2.34 (m, 2H), 2.34-2.19 (m, 2H) 2.13-1.94 (m,1H), 1.94-1.80 (m, 1H). MS (ESI): 537 [M+H]⁺.

Step B:N-{3-[2-Cyclobutyl-5-(2-{[1-(methylsulfonyl)-4-piperidinyl]amino}-4-pyrimidinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide

Following a procedure analogous to the procedure described in Example 1usingN-{3-[5-(2-chloro-4-pyrimidinyl)-2-cyclobutyl-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide(0.10 g, 0.19 mmol) and 1-(methylsulfonyl)-4-piperidinamine (0.33 g, 1.9mmol) in THF (2 mL) the title compound was obtained (0.075 g, 0.11 mmol,59% yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.72 (s, 1H), 8.08-7.97 (m,1H), 7.59-7.18 (m, 7H), 6.17-5.73 (m, 1H), 3.84 (quin, J=8.4 Hz, 1H),3.60-3.39 (m, 2H), 2.93-2.62 (m, 7H), 2.43-2.12 (m, 4H), 2.10-1.68 (m,3H), 1.64-1.29 (m, 2H), m/z (ESI): 679 [M+H]⁺.

Example 822,5-Difluoro-N-{2-fluoro-3-[5-(2-{[1-(methylsulfonyl)-4-piperidinyl]amino}-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]phenyl}benzenesulfonamide

Following a procedure analogous to the procedure described in Example 1usingN-{3-[5-(2-chloro-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide(0.2 g, 0.352 mmol) and 1-(methylsulfonyl)-4-piperidinamine (0.314 g,1.76 mmol) in THF (1 mL) the title compound was obtained as a whitesolid (0.14 g, 0.197 mmol, 56.0% yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm10.75 (s, 1H), 7.90 (d, J=5.2 Hz, 1H), 7.68-7.71 (m, 1H), 7.45-7.63 (m,3H), 7.36-7.45 (m, 1H), 7.21-7.35 (m, 2H), 7.05-7.20 (m, 1H), 3.38-3.78(m, 5H), 3.32 (s, 3H), 2.56-3.18 (m, 4H), 1.38-2.43 (m, 8H). MS (ESI):710 [M+H]⁺.

Example 832,5-Difluoro-N-{2-fluoro-3-[5-{2-[(1-methylethyl)amino]-4-pyrimidinyl}-2-(4-morpholinyl)-1,3-thiazol-4-yl]phenyl}benzenesulfonamide

Following a procedure analogous to the procedure described in Example18, Step B usingN-{3-[5-(2-chloro-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide(0.20 g, 0.35 mmol) and isopropylamine (2 mL) the title compound wasobtained as a yellow solid (0.15 g, 0.25 mmol, 72% yield). ¹H NMR (400MHz, DMSO-d₆) δ ppm 14.28 (br. s., 1H), 8.35 (d, J=7.2 Hz, 1H), 7.84 (s,1H) 7.67-7.51 (m, 2H), 7.47 (d, J=6.8 Hz, 1H), 7.33-7.07 (m, 3H), 5.90(d, J=6.6 Hz, 1H), 4.08 (dq, J=13.3, 6.7 Hz, 1H), 3.88-3.73 (m, 4H),3.71-3.52 (m, 4H), 1.27 (d, J=6.4 Hz, 6H). MS (ESI): 591 [M+H]⁺.

Example 84N-{5-[5-(2-Amino-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-3-fluorobenzenesulfonamide

Step A:N-{5-[5-(2-Chloro-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-3-fluorobenzenesulfonamide

Following a procedure analogous to the procedure described inIntermediate 14 using5-[5-(2-chloro-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]-2-fluoroaniline(12 g, 34.5 mmol) and 3-fluorobenzenesulfonyl chloride (8.72 g, 44.8mmol) the title compound of Step A was obtained (9.3 g, 53.4%). ¹H NMR(400 MHz, CDCl₃) δ ppm 8.35 (d, J=5.3 Hz, 1H), 7.65-7.73 (m, 1H),7.52-7.60 (m, 1H), 7.41-7.50 (m, 2H), 7.20-7.37 (m, 1H), 7.04-7.12 (m,1H), 6.83-7.00 (m, 2H), 3.30-3.40 (m, 1H), 1.46 (d, J=6.8 Hz, 6H). MS(ES+): 507 [M+H]⁺.

Step B:N-{5-[5-(2-Amino-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-3-fluorobenzenesulfonamide

Following a procedure analogous to the procedure described in Example51, Step B usingN-{5-[5-(2-chloro-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-3-fluorobenzenesulfonamide(100 mg, 0.20 mmol) and 7N ammonia in MeOH (2 mL) the title compound wasobtained as a white powder (46 mg, 0.09 mmol, 47.2% yield). ¹H NMR (400MHz, DMSO-d₆) ppm δ 10.48 (s, 1H), 8.07 (d, J=5.1 Hz, 1H), 7.62 (t,J=6.8 Hz, 1H), 7.50-7.55 (m, 3H), 7.34-7.39 (m, 2H), 7.26 (t, J=10.4 Hz,1H), 6.78 (s, 2H), 6.17 (d, J=5.1 Hz, 1H), 3.25-3.30 (m, 1H), 1.36 (d,J=6.8 Hz, 6H). MS (ESI): 487.8 [M+H]⁺.

Example 85N-{4-[4-(3-{[(3-Fluorophenyl)sulfonyl]amino}phenyl)-2-(1-methylethyl)-1,3-thiazol-5-yl]-2-pyrimidinyl}glycine

Step A:N-{3-[5-(2-Chloro-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]phenyl}-3-fluorobenzenesulfonamide

Following a procedure analogous to the procedure described inIntermediate 14 using3-[5-(2-chloro-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]aniline(1.0 g, 3.0 mmol) and 3-fluorobenzenesulfonyl chloride (0.60 mL, 4.5mmol) the title compound of Step A was obtained (1.46 g, 2.99 mmol, 100%yield). ¹H NMR (400 MHz, DMSO-d₆): δ 10.56 (s, 1H), 8.51 (d, J=5.2 Hz,1H), 7.48-7.65 (m, 4H), 7.37 (t, J=7.7 Hz, 1H), 7.20-7.28 (m, 3H), 6.97(d, J=5.1 Hz, 1H), 3.30-3.37 (m, 1H), 1.38 (d, J=7.0 Hz, 6H). MS (ESI):489.1 [M+H]⁺.

Step B:N-{4-[4-(3-{[(3-Fluorophenyl)sulfonyl]amino}phenyl)-2-(1-methylethyl)-1,3-thiazol-5-yl]-2-pyrimidinyl}glycine

To a solution ofN-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]phenyl}-3-fluorobenzenesulfonamide(100 mg, 0.20 mmol) in 1-butanol (5 mL) was added glycine (153 mg, 2.0mmol) and K₂CO₃ (566 mg, 4.0 mmol). The reaction was stirred at 60° C.for 16 h, then partitioned between water and EtOAc. The pH of theaqueous layer was adjusted to below 4 with 1N HCl, and the aqueous layerwas extracted with EtOAc. This organic layer was dried over anhydrousNa₂SO₄, filtered, and concentrated to generate the title compound as awhite powder (24 mg, 0.05 mmol, 22.8% yield). ¹H NMR (400 MHz, DMSO-d₆):δ 8.04 (d, J=4.5 Hz, 1H), 7.46-7.64 (m, 5H), 7.33 (t, J=8.1 Hz, 1H),7.18-7.24 (m, 3H), 6.07 (s, 1H), 3.89 (s, 2H), 3.25-3.29 (m, 1H), 1.36(d, J=6.7 Hz, 6H). MS (ESI): 528.1 [M+H]⁺.

Example 863-Fluoro-N-{3-[5-[2-(methylamino)-4-pyrimidinyl]-2-(1-methylethyl)-1,3-thiazol-4-yl]phenyl}benzenesulfonamide

Following a procedure analogous to the procedure described in Example 1usingN-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]phenyl}-3-fluorobenzenesulfonamide(100 mg, 0.20 mmol), methylamine (2.0M in THF, 2.0 mL, 4.0 mmol) andK₂CO₃ (283 mg, 2.0 mmol) in 1-butanol (5 mL) the title compound wasobtained as a white powder (100 mg, 0.21 mmol, 100% yield). ¹H NMR (400MHz, DMSO-d₆): δ 10.51 (s, 1H), 8.02 (d, J=5.1 Hz, 1H), 7.57-7.65 (m,2H), 7.48-7.53 (m, 2H), 7.33 (t, J=7.8 Hz, 1H), 7.19-7.22 (m, 4H), 6.04(s, 1H), 3.23-3.30 (m, 1H), 2.76 (s, 3H), 1.36 (d, J=6.7 Hz, 6H); m/z(ESI): 485.3 [M+H]⁺.

Example 87N²-{4-[4-(3-{[(3-Fluorophenyl)sulfonyl]amino}phenyl)-2-(1-methylethyl)-1,3-thiazol-5-yl]-2-pyrimidinyl}glycinamide

Following a procedure analogous to the procedure described in Example86, Step B usingN-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]phenyl}-3-fluorobenzenesulfonamide(100 mg, 0.20 mmol) and glycinamide hydrochloride (225 mg, 2.0 mmol) andK₂CO₃ (566 mg, 4.0 mmol) in 1-butanol (5 mL) the title compound wasobtained as a white powder (29 mg, 27.6% yield). ¹H NMR (400 MHz,DMSO-d₆): δ 10.51 (s, 1H), 8.02 (d, J=5.1 Hz, 1H), 7.57-7.65 (m, 2H),7.48-7.53 (m, 2H), 7.33 (t, J=7.8 Hz, 1H), 7.19-7.22 (m, 4H), 6.04 (s,1H), 3.23-3.30 (m, 1H), 2.76 (s, 3H), 1.36 (d, J=6.7 Hz, 6H). MS (ESI):527.1 [M+H]⁺.

Example 88N-{3-[5-(2-{[3-(Dimethylamino)propyl]amino}-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]phenyl}-3-fluorobenzenesulfonamide

Following a procedure analogous to the procedure described in Example 1usingN-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]phenyl}-3-fluorobenzenesulfonamide(100 mg, 0.20 mmol), N,N-dimethyl-1,3-propanediamine (260 μL, 2.0 mmol)and K₂CO₃ (283 mg, 2.0 mmol) in 1-butanol (5 mL) the title compound wasobtained as a white powder (84 mg, 0.15 mmol, 75.8% yield). ¹H NMR (400MHz, DMSO-d₆): δ 8.01 (d, J=5.1 Hz, 1H), 7.45-7.63 (m, 4H), 7.28-7.32(m, 2H), 7.15-7.20 (m, 3H), 6.04 (s, 1H), 3.24-3.31 (m, 3H), 2.31 (t,J=7.1 Hz, 2H), 2.17 (s, 6H), 1.66 (t, J=7.0 Hz, 2H), 1.35 (d, J=6.8 Hz,6H). MS (ESI): 555.3 [M+H]+.

Example 89N-{3-[5-[2-(Cyclopropylamino)-4-pyrimidinyl]-2-(1-methylethyl)-1,3-thiazol-4-yl]phenyl}-3-fluorobenzenesulfonamide

Following a procedure analogous to the procedure described in Example 1usingN-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]phenyl}-3-fluorobenzenesulfonamide(100 mg, 0.20 mmol) and cyclopropylamine (141 μL, 2.0 mmol) and K₂CO₃(283 mg, 2.0 mmol) in 1-butanol (5 mL) the title compound was obtainedas a white powder (43 mg, 0.08 mmol, 42.2% yield). ¹H NMR (400 MHz,DMSO-d₆): δ 10.51 (s, 1H), 8.05 (d, J=5.0 Hz, 1H), 7.48-7.65 (m, 5H),7.33 (t, J=7.4 Hz, 1H), 7.19-7.23 (m, 3H), 6.09 (d, J=4.7 Hz, 1H),3.25-3.30 (m, 1H), 2.67 (bs, 1H), 1.35 (d, J=7.0 Hz, 6H), 0.63 (d, J=4.7Hz, 2H), 0.46 (bs, 2H). MS (ESI): 510.4 [M+H]+.

Example 90N-{3-[5-(2-Amino-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]phenyl}-2,6-difluorobenzenesulfonamide

Following a procedure analogous to the procedure described in Example51, Step B usingN-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]phenyl}-2,6-difluorobenzenesulfonamide(200 mg, 0.39 mmol) in 7N ammonia in MeOH (2 mL) the title compound wasobtained as a white powder (0.16 g, 0.328 mmol, 84.2% yield). ¹H NMR(400 MHz, DMSO-d₆): δ 11.03 (s, 1H), 7.95 (d, J=5.1 Hz, 1H), 7.68-7.72(m, 1H), 7.35 (t, J=7.7 Hz, 1H), 7.18-7.28 (m, 5H), 6.76 (s, 2H), 6.00(d, J=5.1 Hz, 1H), 3.25-3.31 (m, 1H), 1.36 (d, J=7.0 Hz, 6H). MS (ESI):488.1 [M+H]+.

Example 912,6-Difluoro-N-{2-fluoro-3-[5-{2-[(2-methylpropyl)amino]-4-pyrimidinyl}-2-(4-morpholinyl)-1,3-thiazol-4-yl]phenyl}benzenesulfonamide

Following a procedure analogous to the procedure described in Example18, Step B usingN-{3-[5-(2-chloro-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide(100 mg, 0.176 mmol) and isobutylamine (2 mL) the title compound wasobtained as a yellow powder (90 mg, 0.149 mmol, 85% yield). ¹H NMR (400MHz, DMSO-d₆): δ 10.87 (s, 1H), 7.86 (d, J=5.3 Hz, 1H), 7.67 (t, J=6.1Hz, 1H), 7.42 (t, J=7.6 Hz, 1H), 7.21-7.31 (m, 4H), 7.14 (bs, 1H), 5.62(bs, 1H), 3.71 (t, J=4.7 Hz, 4H), 3.45 (t, J=4.8 Hz, 4H), 3.02 (bs, 2H),1.78-1.86 (m, 1H), 0.87 (d, J=6.6 Hz, 6H). MS (ESI): 603 [M−H]−.

Example 92N-[3-(2-(1,1-Dimethylethyl)-5-{2-[(2-methylpropyl)amino]-4-pyrimidinyl}-1,3-thiazol-4-yl)-2-fluorophenyl]-2,5-difluorobenzenesulfonamide

Following a procedure analogous to the procedure described in Example18, Step B usingN-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide(100 mg, 0.186 mmol) and isobutylamine (2 mL) the title compound wasobtained as a white powder (52 mg, 48.7% yield). ¹H NMR (400 MHz,DMSO-d₆): δ 10.76 (s, 1H), 8.04 (d, J=5.2 Hz, 1H), 7.35-7.57 (m, 6H),7.28 (t, J=7.8 Hz, 1H), 5.84 (bs, 1H), 2.95 (bs, 2H), 1.80 (bs, 1H),1.40 (s, 9H), 0.86 (d, J=5.5 Hz, 6H). MS (ESI): 574 [M−H]−.

Example 93N-{5-[5-{2-[(2,2-Difluoroethyl)amino]-4-pyrimidinyl}-2-(1-methylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide

Following a procedure analogous to the procedure described in Example18, Step B usingN-{5-[5-(2-chloro-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide(100 mg, 0.190 mmol) and 2,2-difluoroethylamine (300 μL, 3.92 mmol) thetitle compound was obtained as a white powder (57 mg, 0.100 mmol, 52.5%yield). ¹H NMR (400 MHz, DMSO-d₆): δ 10.94 (s, 1H), 8.15 (d, J=5.1 Hz,1H), 7.65-7.75 (m, 2H), 7.38-7.44 (m, 2H), 7.27 (q, J=7.5 Hz, 3H), 6.30(bs, 1H), 3.63 (bs, 2H), 3.27-3.31 (m, 1H), 1.36 (d, J=7.0 Hz, 6H). MS(ESI): 569.9 [M+H]+.

Example 94N-[3-(2-(1,1-Dimethylethyl)-5-{2-[(2,2,2-trifluoroethyl)amino]-4-pyrimidinyl}-1,3-thiazol-4-yl)-2-fluorophenyl]-2,5-difluorobenzenesulfonamide

Following a procedure analogous to the procedure described in Example18, Step B usingN-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide(100 mg, 0.190 mmol) and 2,2,2-trifluoroethylamine (0.5 ml, 0.190 mmol)the title compound, was obtained as a white powder (70 mg, 0.116 mmol,62.7% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 10.78 (s, 1H), 8.49 (d, J=5.2Hz, 1H), 7.37-7.51 (m, 4H), 7.21-7.29 (m, 2H), 6.72 (d, J=5.2 Hz, 1H),4.85 (q, J=8.9 Hz, 2H), 1.42 (s, 9H). MS (ESI): 602.9 [M+H]+.

Example 952,6-Difluoro-N-{2-fluoro-5-[2-(1-methylethyl)-5-(2-{[3-(2-oxo-1-pyrrolidinyl)propyl]amino}-4-pyrimidinyl)-1,3-thiazol-4-yl]phenyl}benzenesulfonamide

Following a procedure analogous to the procedure described in Example 1usingN-{5-[5-(2-chloro-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide(0.15 g, 0.29 mmol) and 1-(3-aminopropyl)-2-pyrrolidinone (0.60 ml, 4.3mmol) the title compound was obtained (0.070 g, 37% yield); ¹H NMR (400MHz, DMSO-d₆) δ ppm 10.92 (s, 1H), 8.08 (d, J=5.0 Hz, 1H), 7.65-7.79 (m,1H), 7.35-7.49 (m, 2H), 7.19-7.34 (m, 4H), 6.11-6.26 (m, 1H), 3.22 (t,J=6.8 Hz, 4H), 2.21 (t, J=8.1 Hz, 2H), 1.91 (quin, J=7.6 Hz, 2H),1.63-1.74 (m, 2H), 1.36 (d, J=6.9 Hz, 6H). MS (ES+): 631 [M+H]⁺.

Example 96N-{3-[2-(1,1-Dimethylethyl)-5-(2-{[3-(2-oxo-1-pyrrolidinyl)propyl]amino}-4-pyrimidinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide

Following a procedure analogous to the procedure described in Example 1usingN-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide(0.20 g, 0.37 mmol) and 1-(3-aminopropyl)-2-pyrrolidinone (0.52 ml, 3.7mmol) the title compound was obtained (0.20 g, 80% yield). ¹H NMR (400MHz, DMSO-d₆) δ ppm 10.75 (s, 1H), 8.03 (d, J=5.1 Hz, 1H), 7.15-7.64 (m,7H), 5.81-5.98 (m, 1H), 3.21 (t, J=6.6 Hz, 2H), 3.07-3.16 (m, 2H), 2.21(t, J=8.0 Hz, 2H), 1.92 (quin, J=7.4 Hz, 2H), 1.66 (br. s., 2H), 1.40(s, 9H). MS (ES+): 645 [M+H]⁺.

Example 97N-{3-[2-(1,1-Dimethylethyl)-5-(2-{[2-(2-oxo-1-pyrrolidinyl)ethyl]amino}-4-pyrimidinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide

A mixture ofN-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide(0.15 g, 0.28 mmol), 1-(2-aminoethyl)-2-pyrrolidinone (0.18 g, 0.83mmol) and DIEA (0.10 ml, 0.56 mmol) in MeOH (0.5 ml) was heated at 50°C. for 2 h. LCMS analysis indicated that the reaction was proceedingvery slowly, another equivalent amine and DIEA was added and thereaction was heated overnight. LCMS analysis indicated the reaction hadstill not progressed sufficiently so the reaction was heated overnightagain. LCMS analysis indicated the reaction had progressed sufficientlyso the reaction mixture was concentrated onto silica gel and purified byflash chromatography to afford a colourless foam. The product wasdissolved in DCM and washed with HCl (10% Aq.) to remove some residualDIEA and the organics were dried over MgSO₄, filtered and the filtratewas concentrated in vacuo to afford the title compound (0.12 g, 67%yield); ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.77 (s, 1H), 8.07 (d, J=5.1Hz, 1H), 7.22-7.65 (m, 7H), 3.21-3.45 (m, 6H), 2.11-2.22 (m, 2H),1.82-1.93 (m, 2H), 1.41 (s, 9H). MS (ES+): 631 [M+H]⁺.

Example 98N-[2-({4-[4-(3-{[(2,5-Difluorophenyl)sulfonyl]amino}-2-fluorophenyl)-2-(1,1-dimethylethyl)-1,3-thiazol-5-yl]-2-pyrimidinyl}amino)ethyl]-2-hydroxyacetamide

Step A:1,1-Dimethylethyl[2-({4-[4-(3-{[(2,5-difluorophenyl)sulfonyl]amino}-2-fluorophenyl)-2-(1,1-dimethylethyl)-1,3-thiazol-5-yl]-2-pyrimidinyl}amino)ethyl]carbamate

Following a procedure analogous to the procedure described in Example 1usingN-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide(0.30 g, 0.56 mmol), 1,1-dimethylethyl (2-aminoethyl)carbamate (0.089 g,0.56 mmol) the title compound of Step A was obtained (0.34 g, 88%yield). ¹H NMR (400 MHz, DMSO-d6) δ ppm 10.75 (s, 1H), 8.03 (d, J=5.1Hz, 1H), 7.13-7.67 (m, 7H), 6.85 (br. s., 1H), 5.80-6.02 (m, 1H),3.16-3.28 (m, 2H), 2.99-3.13 (m, 2H), 1.40 (s, 9H), 1.37 (s, 9H); m/z(ES+): 663 [M+H]⁺.

Step B:N-{3-[5-{2-[(2-Aminoethyl)amino]-4-pyrimidinyl}-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide

A 4N solution of HCl in 1,4-dioxane (1.7 ml, 7.1 mmol) was added to astirring solution of1,1-dimethylethyl[2-({4-[4-(3-{[(2,5-difluorophenyl)sulfonyl]amino}-2-fluorophenyl)-2-(1,1-dimethylethyl)-1,3-thiazol-5-yl]-2-pyrimidinyl}amino)ethyl]carbamate(0.31 g, 0.47 mmol) (composite batches prepared as described in theprevious step) in DCM (10 ml) at rt. MeOH (1 ml) was added to aid insolubility. The reaction was allowed to stir at rt for 3 h. Thevolatiles were removed and the residue was dried in vacuo to afford thetitle compound of Step B (0.31 g, quantitative yield) as a hydrochloridesalt that was used without further purification; ¹H NMR (400 MHz,DMSO-d₆) δ ppm 10.77 (s, 1H), 7.93-8.18 (m, 4H), 7.20-7.69 (m, 7H),3.37-3.53 (m, 2H), 2.96 (d, J=5.1 Hz, 2H), 1.41 (s, 9H). MS (ES+): 563[M+H]⁺.

Step C:N-[2-({4-[4-(3-{[(2,5-Difluorophenyl)sulfonyl]amino}-2-fluorophenyl)-2-(1,1-dimethylethyl)-1,3-thiazol-5-yl]-2-pyrimidinyl}amino)ethyl]-2-hydroxyacetamide

A mixture of glycolic acid (0.040 g, 0.50 mmol), HATU (0.19 g, 0.50mmol) and DIEA (0.09 ml, 0.50 mmol) in DMF (1 mL) was added to astirring solution ofN-{3-[5-{2-[(2-aminoethyl)amino]-4-pyrimidinyl}-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide(0.15 g, 0.25 mmol) and DIEA (0.09 ml, 0.50 mmol) in DMF (1 mL). Thereaction was stirred for 1 h. LCMS analysis indicated approximately 50%conversion to product. An additional 2.0 equivalents of activatedglycolic acid was added and the reaction was allowed to stir for anadditional 1 h. LCMS analysis indicated the starting material was stillnot completely consumed so an additional 2.0 equivalents of activatedglycolic acid was added and the reaction was stirred for an addition 1h. The reaction was diluted with EtOAc, washed with water (×5) and asaturated aqueous brine solution (×2). The organic layer was dried overMgSO₄, filtered and the filtrate was concentrated onto silca gel andpurified by flash chromatography to afford the title compound (0.072 g,44% yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.75 (br. s., 1H), 8.04 (d,J=5.1 Hz, 1H), 7.77-7.98 (m, 1H), 7.15-7.65 (m, 7H), 5.81-6.01 (m, 1H),5.49 (t, J=5.2 Hz, 1H), 3.80 (d, J=5.3 Hz, 2H), 3.29 (br. s., 2H), 1.40(s, 9H). MS (ES+): 621 [M+H]⁺.

Example 99N-(3-{5-(2-Amino-4-pyrimidinyl)-2-[4-(methylsulfonyl)-1-piperazinyl]-1,3-thiazol-4-yl}-2-fluorophenyl)-2,5-difluorobenzenesulfonamide

Step A: 1,1-Dimethylethyl 4-(aminocarbonothioyl)-1-piperazinecarboxylate

1,1-Dimethylethyl 1-piperazinecarboxylate (24 g, 129 mmol) in THF (1 L)was treated with 4N HCl in dioxane (32.2 mL, 129 mmol)), and thiocyanate(12.52 g, 129 mmol) dissolved in minimal amount of water was added.After stirring at rt overnight, the volatiles were removed under reducedpressure. The residue was taken up in MeOH and filtered to removeinorganic salts and the solvent removed in vacuo and the cycle wasrepeated 3 more times. Then twice taken up in DCM and filtered andconcentrated to give the title compound of Step A (29 g, 92% yield). ¹HNMR (400 MHz, DMSO-d₆) δ ppm 8.74 (br. s., 2H), 3.50 (br. s., 4H), 3.07(t, J=5.0 Hz, 4H), 1.40 (s, 9H).

Step B: 1,1-Dimethylethyl4-[5-(2-chloro-4-pyrimidinyl)-4-(3-{[(2,5-difluorophenyl)sulfonyl]amino}-2-fluorophenyl)-1,3-thiazol-2-yl]-1-piperazinecarboxylate

NBS (0.21 g, 1.2 mmol) was added to a stirring solution ofN-(3-(2-(2-chloropyrimidin-4-yl)acetyl)-2-fluorophenyl)-2,5-difluorobenzenesulfonamide(0.50 g, 1.13 mmol) in DMA (5.5 ml) at rt. The reaction was allowed tostir for 15 min, then 1,1-dimethylethyl4-(aminocarbonothioyl)-1-piperazinecarboxylate (0.55 g, 2.26 mmol) wasadded and the reaction was allowed to stir for 1 h. LCMS analysisindicated the reaction had progressed sufficiently, the reaction waspoured into water and the bright yellow precipitate was collected byfiltration. The filter cake was dissolved in DCM, dried over MgSO₄,filtered and the filtrate was concentrated onto silica gel. Purificationby flash chromatography afforded the title compound of Step B (0.36 g,45% yield) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.79 (s,1H), 8.32 (d, J=5.5 Hz, 1H), 7.25-7.64 (m, 6H), 6.47 (d, J=5.5 Hz, 1H),3.53-3.58 (m, 4H), 3.43-3.51 (m, 4H), 1.42 (s, 9H).

Step C:N-{3-[5-(2-Chloro-4-pyrimidinyl)-2-(1-piperazinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide

A 4N solution of HCl in 1,4-dioxane (1.1 ml, 4.3 mmol) was added to astirring solution of 1,1-dimethylethyl4-[5-(2-chloro-4-pyrimidinyl)-4-(3-{[(2,5-difluorophenyl)sulfonyl]amino}-2-fluorophenyl)-1,3-thiazol-2-yl]-1-piperazinecarboxylate(0.36 g, 0.54 mmol) in DCM (8 mL) and MeOH (1 mL) at rt. The reactionwas allowed to stir overnight. LCMS analysis indicated completeconsumption of the starting material. The volatiles were removed invaccuo to afford the HCl salt of the desired product of Step C (0.40 g,100% yield) which was carried forward without further purification. MS(ES+): 568 [M+H]⁺.

Step D:N-(3-{5-(2-Chloro-4-pyrimidinyl)-2-[4-(methylsulfonyl)-1-piperazinyl]-1,3-thiazol-4-yl}-2-fluorophenyl)-2,5-difluorobenzenesulfonamide

Methanesulfonyl chloride (0.05 mL, 0.7 mmol) was added to a stirringsolution ofN-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1-piperazinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide(0.40 g, 0.66 mmol) and TEA (0.32 mL, 2.3 mmol) in DCM (10 mL) at rt.LCMS analysis indicated clean conversion to product. The reaction wasquenched with water and the whole was extracted with DCM. The combinedorganic extracts were dried over MgSO₄, filtered, and the filtrate wasconcentrated onto silica gel. Purification by flash chromatographyafforded the title compound of Step D (0.14 g, 30% yield). ¹H NMR (400MHz, DMSO-d₆) δ ppm 10.80 (s, 1H), 8.34 (d, J=5.5 Hz, 1H), 7.25-7.63 (m,5H), 6.50 (d, J=5.3 Hz, 1H), 3.69 (br. s., 4H), 3.27 (br. s., 4H), 2.93(s, 3H).

Step E:N-(3-{5-(2-Amino-4-pyrimidinyl)-2-[4-(methylsulfonyl)-1-piperazinyl]-1,3-thiazol-4-yl}-2-fluorophenyl)-2,5-difluorobenzenesulfonamide

A solution ofN-(3-{5-(2-chloro-4-pyrimidinyl)-2-[4-(methylsulfonyl)-1-piperazinyl]-1,3-thiazol-4-yl}-2-fluorophenyl)-2,5-difluorobenzenesulfonamide(0.14 g, 0.22 mmol) in NH₄OH (2.5 mL, 65 mmol) was sealed in a microwavevial and irradiated at 140° C. for 12 min. LCMS analysis indicatescomplete conversion to product. The reaction mixture was transferred toa round bottom flask with DCM and MeOH. A precipitate formed whileattempting to remove the volatiles in vacuo and it was collected byvacuum filtration. The pale yellow solid was dried in vacuo to affordthe title compound (0.14 g, 100% yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm10.76 (br. s., 1H), 7.84 (d, J=5.3 Hz, 1H), 7.46-7.61 (m, 3H), 7.38-7.46(m, 1H), 7.22-7.34 (m, 2H), 6.59 (br. s., 2H), 5.64 (d, J=5.1 Hz, 1H),3.60 (br. s., 4H), 3.26 (br. s., 4H), 2.92 (s, 3H). MS (ES+): 626[M+H]⁺.

Example 100N-(3-{5-(2-Amino-4-pyrimidinyl)-2-[4-(methylsulfonyl)-1-piperazinyl]-1,3-thiazol-4-yl}-2-fluorophenyl)-2,6-difluorobenzenesulfonamide

Step A: 1,1-Dimethylethyl4-[5-(2-chloro-4-pyrimidinyl)-4-(3-{[(2,6-difluorophenyl)sulfonyl]amino}-2-fluorophenyl)-1,3-thiazol-2-yl]-1-piperazinecarboxylate

Following a procedure analogous to Intermediate 6 usingN-{3-[(2-chloro-4-pyrimidinyl)acetyl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide(2.00 g, 4.53 mmol), NBS (0.85 g, 4.75 mmol) and 1,1-dimethylethyl4-(aminocarbonothioyl)-1-piperazinecarboxylate (2.22 g, 9.05 mmol) thetitle compound of Step A was obtained (1.16 g, 38% yield). ¹H NMR (400MHz, DMSO-d6) δ ppm 10.93 (s, 1H), 8.30 (d, J=5.49 Hz, 1H), 7.62-7.76(m, 1H), 7.46 (td, J=7.46, 1.28 Hz, 1H), 7.38 (t, J=6.09 Hz, 1H), 7.32(t, J=7.78 Hz, 1H), 7.25 (t, J=9.11 Hz, 2H), 6.46 (d, J=5.40 Hz, 1H),3.56 (br. s., 4H), 3.47 (br. s., 4H), 1.42 (s, 9H). m/z (ES+): 668[M+H]⁺.

Step B:N-{3-[5-(2-Chloro-4-pyrimidinyl)-2-(1-piperazinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide

To 1,1-dimethylethyl4-[5-(2-chloro-4-pyrimidinyl)-4-(3-{[(2,6-difluorophenyl)sulfonyl]amino}-2-fluorophenyl)-1,3-thiazol-2-yl]-1-piperazinecarboxylate(1.13 g, 1.694 mmol) in DCM (20 mL) was treated with TFA (20 mL) at rtfor 30 min. The reaction mixture was concentrated and the residue wastriturated with DCM and hexane to give (1.10 g, 95% yield) of the titlecompound of Step B. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.95 (br. s., 1H),9.04 (br. s., 1H), 8.34 (d, J=5.5 Hz, 1H), 7.63-7.76 (m, 1H), 7.42-7.49(m, 1H), 7.38 (t, J=6.1 Hz, 1H), 7.30-7.36 (m, 1H), 7.26 (t, J=9.2 Hz,2H), 6.52 (d, J=5.4 Hz, 1H), 3.77 (d, J=4.8 Hz, 4H), 3.27 (br. s., 4H).m/z (ES+): 568 [M+H]⁺.

Step C:N-(3-{5-(2-Chloro-4-pyrimidinyl)-2-[4-(methylsulfonyl)-1-piperazinyl]-1,3-thiazol-4-yl}-2-fluorophenyl)-2,6-difluorobenzenesulfonamide

N-{3-[5-(2-Chloro-4-pyrimidinyl)-2-(1-piperazinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide(0.50 g, 0.734 mmol) in DCM (10 mL) was treated with methanesulfonylchloride (0.074 mL, 0.954 mmol) and stirred at rt for 3 h. Silica wasadded and concentrated. The residue was column chromatographed withEtOAc/DCM to give title compound of Step C (0.38 g, 96% yield). ¹H NMR(400 MHz, DMSO-d₆) δ ppm 10.93 (s, 1H), 8.32 (d, J=5.5 Hz, 1H),7.64-7.74 (m, 1H), 7.42-7.50 (m, 1H), 7.39 (t, J=6.1 Hz, 1H), 7.29-7.35(m, 1H), 7.25 (t, J=9.1 Hz, 2H), 6.49 (d, J=5.4 Hz, 1H), 3.63-3.76 (m,4H), 3.27 (t, J=4.7 Hz, 4H), 2.93 (s, 3H). m/z (ES+): 646 [M+H]⁺.

Step D:N-(3-{5-(2-Amino-4-pyrimidinyl)-2-[4-(methylsulfonyl)-1-piperazinyl]-1,3-thiazol-4-yl}-2-fluorophenyl)-2,6-difluorobenzenesulfonamide

Following a procedure analogous to Example 51, Step B usingN-(3-{5-(2-chloro-4-pyrimidinyl)-2-[4-(methylsulfonyl)-1-piperazinyl]-1,3-thiazol-4-yl}-2-fluorophenyl)-2,6-difluorobenzenesulfonamide(0.140 g, 0.217 mmol) and 7M ammonia in MeOH (25 mL) the title compoundwas obtained (0.041 g, 30% yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.88(br. s., 1H), 7.84 (d, J=5.3 Hz, 1H), 7.63-7.73 (m, 1H), 7.37-7.48 (m,1H), 7.17-7.34 (m, 4H), 6.58 (br. s., 2H), 5.65 (d, J=5.2 Hz, 1H), 3.60(br. s., 4H), 3.26 (br. s., 4H), 2.92 (s, 3H). m/z (ES+): 626 [M+H]⁺.

Example 101N-(3-{5-(2-Amino-4-pyrimidinyl)-2-[1-(methylsulfonyl)-4-piperidinyl]-1,3-thiazol-4-yl}-2-fluorophenyl)-2,5-difluorobenzenesulfonamide

Step A: 1,1-Dimethylethyl4-[5-(2-chloro-4-pyrimidinyl)-4-(3-{[(2,5-difluorophenyl)sulfonyl]amino}-2-fluorophenyl)-1,3-thiazol-2-yl]-1-piperidinecarboxylate

Following a procedure analogous to Intermediate 6 usingN-(3-(2-(2-chloropyrimidin-4-yl)acetyl)-2-fluorophenyl)-2,5-difluorobenzenesulfonamide(4.80 g, 10.86 mmol) and 1,1-dimethylethyl4-(aminocarbonothioyl)-1-piperidinecarboxylate (3.19 g, 13.04 mmol) thetitle compound of Step A was obtained (4.31 g, 60% yield). ¹H NMR (400MHz, DMSO-d₆) δ ppm 10.78 (s, 1H), 8.57 (d, J=5.3 Hz, 1H), 7.36-7.68 (m,5H), 7.32 (t, J=7.8 Hz, 1H), 6.90 (d, J=5.3 Hz, 1H), 4.01 (d, J=11.4 Hz,2H), 3.20-3.34 (m, 1H), 2.92 (d, J=12.6 Hz, 2H), 2.07 (d, J=11.3 Hz,2H), 1.52-1.70 (m, 2H), 1.40 (s, 9H). m/z (ES+): 667 [M+H]⁺.

Step B:N-{3-[5-(2-Chloro-4-pyrimidinyl)-2-(4-piperidinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide

Following a procedure analogous to Example 100, Step B using1,1-dimethylethyl4-[5-(2-chloro-4-pyrimidinyl)-4-(3-{[(2,5-difluorophenyl)sulfonyl]amino}-2-fluorophenyl)-1,3-thiazol-2-yl]-1-piperidinecarboxylate(2.00 g, 3.00 mmol) the title compound of Step B was obtained (1.80 g,88% yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.81 (s, 1H), 8.86 (d,J=9.6 Hz, 1H), 8.48-8.66 (m, 2H), 7.38-7.65 (m, 5H), 7.33 (t, J=7.8 Hz,1H), 6.92 (d, J=5.2 Hz, 1H), 3.32-3.54 (m, 2H), 2.97-3.15 (m, 2H), 2.26(d, J=12.2 Hz, 2H), 1.80-1.97 (m, 2H). m/z (ES+): 567 [M+H]⁺.

Step C:N-(3-{5-(2-Amino-4-pyrimidinyl)-2-[1-(methylsulfonyl)-4-piperidinyl]-1,3-thiazol-4-yl}-2-fluorophenyl)-2,5-difluorobenzenesulfonamide

ToN-{3-[5-(2-chloro-4-pyrimidinyl)-2-(4-piperidinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide(0.30 g, 0.441 mmol) in DCM (5 mL) was added methanesulfonyl chloride(0.038 mL, 0.485 mmol) at rt and stirred for 3 h. The reaction mixturewas concentrated with silica and was chromatographed to give thesulfonamide compound (0.17 g, 0.261 mmol), which was treated with NH₄OH(6 mL, 154 mmol) and microwave irradiated at 130° C. for 30 min. Thereaction was concentrated onto silica and column chromatographed to givethe title compound (0.12 g, 71%). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.77(s, 1H), 7.99 (d, J=5.1 Hz, 1H), 7.20-7.62 (m, 6H), 6.78 (s, 2H), 5.85(d, J=5.1 Hz, 1H), 3.63 (d, J=12.1 Hz, 2H), 3.10-3.23 (m, 1H), 2.84-2.96(m, 5H), 2.18 (d, J=11.1 Hz, 2H), 1.66-1.82 (m, 2H). m/z (ES+): 625[M+H]⁺.

Example 102N-{3-[5-(2-Amino-4-pyrimidinyl)-2-(1,1-dioxido-4-thiomorpholinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide

Step A:N-{3-[5-(2-Chloro-4-pyrimidinyl)-2-(1,1-dioxido-4-thiomorpholinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide

Following a procedure analogous to Intermediate 6 usingN-{3-[(2-chloro-4-pyrimidinyl)acetyl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide(1.5 g, 3.40 mmol), NBS (0.60 g, 3.40 mmol) and4-thiomorpholinecarbothioamide 1,1-dioxide (0.80 g, 4.12 mmol) the titlecompound of Step A was obtained (1.88 g, 90% yield). ¹H NMR (400 MHz,DMSO-d₆) δ ppm 10.94 (br. s., 1H), 8.34 (d, J=5.1 Hz, 1H), 7.59-7.78 (m,1H), 7.37-7.52 (m, 2H), 7.32 (t, J=7.7 Hz, 1H), 7.25 (t, J=9.1 Hz, 2H),6.55 (d, J=4.9 Hz, 1H), 4.04 (br. s., 4H), 3.32 (br. s., 4H). m/z (ES+):617 [M+H]⁺.

Step B:N-{3-[5-(2-Amino-4-pyrimidinyl)-2-(1,1-dioxido-4-thiomorpholinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide

Following a procedure analogous to Example 51, Step B usingN-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dioxido-4-thiomorpholinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide(0.30 g, 0.487 mmol) and 7M ammonia (20 mL) the title compound wasobtained (0.11 g, 38% yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.88 (br.s., 1H), 7.85 (d, J=5.3 Hz, 1H), 7.63-7.75 (m, 1H), 7.42 (td, J=7.5, 1.7Hz, 1H), 7.19-7.36 (m, 4H), 6.60 (br. s., 2H), 5.68 (d, J=5.1 Hz, 1H),3.97 (br. s., 4H), 3.29 (br. s., 4H). m/z (ES+): 597 [M+H]⁺.

Example 103N-(3-{5-(2-Amino-4-pyrimidinyl)-2-[(2R,6S)-2,6-dimethyl-4-morpholinyl]-1,3-thiazol-4-yl}-2-fluorophenyl)-2,5-difluorobenzenesulfonamide

Step A:N-(3-{5-(2-Chloro-4-pyrimidinyl)-2-[(2R,6S)-2,6-dimethyl-4-morpholinyl]-1,3-thiazol-4-yl}2-fluorophenyl)-2,5-difluorobenzenesulfonamide

ToN-(3-(2-(2-chloropyrimidin-4-yl)acetyl)-2-fluorophenyl)-2,5-difluorobenzenesulfonamide(1.5 g, 3.40 mmol) was added DMA (10 mL) and NBS (0.61 g, 3427 mmol).After stirring at rt for 10 min,(2R,6S)-2,6-dimethyl-4-morpholinecarbothioamide (0.800 g, 4.59 mmol) wasadded and stirring continued for 2 h. Water was added and the solid wascollected by filtration and dried over two days to afford the titlecompound of Step A (1.80 g, 89% yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm10.80 (s, 1H), 8.31 (d, J=5.4 Hz, 1H), 7.49-7.63 (m, 3H), 7.45 (t, J=7.6Hz, 1H), 7.39 (t, J=6.4 Hz, 1H), 7.31 (t, J=7.8 Hz, 1H), 6.46 (d, J=5.3Hz, 1H), 3.88 (d, J=11.4 Hz, 1H), 3.66 (br. s., 1H), 2.94 (s, 2H), 2.78(s, 2H), 1.14 (d, J=6.0 Hz, 6H). m/z (ES+): 597 [M+H]⁺.

Step B:N-(3-{5-(2-Amino-4-pyrimidinyl)-2-[(2R,6S)-2,6-dimethyl-4-morpholinyl]-1,3-thiazol-4-yl}-2-fluorophenyl)-2,5-difluorobenzenesulfonamide

In a pressure vessel was placedN-(3-{5-(2-chloro-4-pyrimidinyl)-2-[(2R,6S)-2,6-dimethyl-4-morpholinyl]-1,3-thiazol-4-yl}-2-fluorophenyl)-2,5-difluorobenzenesulfonamide(0.30 g, 0.503 mmol) and NH₄OH (3 mL, 77 mmol) and 1,4-dioxane (3 mL)were added. The vessel was sealed and heated at 100° C. for 18 h. Thereaction was cooled, concentrated onto silica and the residue was columnchromatographed to give the title compound was obtained (0.22 g, 75%yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.77 (br. s., 1H), 7.82 (d,J=5.3 Hz, 1H), 7.46-7.65 (m, 3H), 7.37-7.46 (m, 1H), 7.27 (t, J=6.7 Hz,2H), 6.54 (br. s., 2H), 5.62 (d, J=5.3 Hz, 1H), 3.77 (d, J=12.2 Hz, 2H),3.60-3.73 (m, 2H), 2.73 (t, J=11.6 Hz, 2H), 1.14 (d, J=6.0 Hz, 6H). m/z(ES+): 577 [M+H]⁺.

Example 104N-{3-[5-(2-Amino-4-pyrimidinyl)-2-cyclohexyl-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide

Step A: Cyclohexanecarbothioamide

Cyclohexanecarboxamide (1 g, 7.86 mmol) and Lawesson's Reagent (2 g,4.94 mmol) in THF (50 mL) was heated at 70° C. for 3 h. Silica was addedand the volatiles were removed under reduced pressure. The residue wascolumn chromatographed with EtOAc/DCM to affordcyclohexanecarbothioamide (0.557 g, 49% yield). ¹H NMR (400 MHz, CDCl₃)δ ppm 7.67 (br. s., 1H), 6.91 (br. s., 1H), 2.56 (tt, J=11.8, 3.3 Hz,1H), 1.90-2.02 (m, 2H), 1.78-1.90 (m, 2H), 1.71 (d, J=12.0 Hz, 1H), 1.51(qd, J=12.3, 2.8 Hz, 2H), 1.16-1.40 (m, 3H), e/z (ES+): 144 [M+H]⁺.

Step B:N-{3-[5-(2-Chloro-4-pyrimidinyl)-2-cyclohexyl-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide

Following a procedure analogous to Intermediate 6 usingN-{3-[(2-chloro-4-pyrimidinyl)acetyl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide(0.45 g, 1.019 mmol) and cyclohexanecarbothioamide (0.18 mg, 1.23 mmol)the title compound of Step B was obtained (0.38 g, 66% yield). ¹H NMR(400 MHz, DMSO-d₆) δ ppm 10.92 (s, 1H), 8.54 (d, J=5.3 Hz, 1H),7.61-7.75 (m, 1H), 7.39-7.50 (m, 2H), 7.32 (t, J=7.9 Hz, 1H), 7.24 (t,J=9.1 Hz, 2H), 6.86 (d, J=5.3 Hz, 1H), 2.96-3.12 (m, 1H), 2.09 (d,J=10.6 Hz, 2H), 1.78 (dd, J=9.7, 3.2 Hz, 2H), 1.68 (d, J=12.5 Hz, 1H),1.47-1.61 (m, 2H), 1.33-1.45 (m, 2H), 1.21-1.32 (m, 1H). m/z (ES+): 566[M+H]⁺.

Step C:N-{3-[5-(2-Amino-4-pyrimidinyl)-2-cyclohexyl-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide

Following a procedure analogous to Example 21 usingN-{3-[5-(2-chloro-4-pyrimidinyl)-2-cyclohexyl-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide(0.10 g, 0.177 mmol) and NH₄OH (3 mL) the title compound was obtained(0.055 g, 57% yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.88 (br. s.,1H), 7.97 (br. s., 1H), 7.68 (br. s., 1H), 7.09-7.57 (m, 5H), 6.75 (br.s., 2H), 5.84 (br. s., 1H), 2.98 (d, J=0.5 Hz, 1H), 2.06 (br. s., 2H),1.59-1.91 (m, 3H), 1.06-1.59 (m, 5H). m/z (ES+): 546 [M+H]⁺.

Example 105N-{3-[5-(2-Amino-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]-2,4-difluorophenyl}-2,5-difluorobenzenesulfonamide

Step A: Methyl 2,6-difluorobenzoate

To a suspension of carboxylic acid (50 g, 316 mmol) in MeOH (800 mL) wasadded TsOH (6 g, 10%), the mixture was heated to reflux overnight. TLCshows reaction complete. The solvent was removed under reduced pressure.The residue was dissolved in EtOAc and washed by saturated NaHCO₃ andbrine successively. The organic layer was separated, dried over Na₂SO₄and concentrated under reduced pressure to give methyl2,6-difluorobenzoate (41 g, 75.9% yield). ¹H NMR (400 MHz, CDCl₃) δ ppm7.37-7.46 (m, 1H), 6.91-6.98 (m, 2H), 3.95 (s, 3H).

Step B: Methyl 2,6-difluoro-3-nitrobenzoate

Fuming nitric acid (11 g, 174 mmol) was added to a solution of methyl2,6-difluorobenzoate (25 g, 145 mmol) in concentrated sulfuric acid (50mL) at 0° C., and the reaction was stirred for 30 min at 0° C. Thereaction mixture was poured over ice-water. The precipitate was filteredoff by suction to give the desired product of Step B (25.1 g, 80.6%). ¹HNMR (400 MHz, CDCl₃) δ ppm 8.13-8.20 (m, 1H), 7.02-7.10 (m, 1H), 3.93(s, 3H).

Step C: Methyl 3-amino-2,6-difluorobenzoate

To a solution of methyl 2,6-difluoro-3-nitrobenzoate (25 g, 115 mmol) inMeOH (150 mL) was added 5% palladium on carbon (2.5 g). The mixture wasstirred under H₂ atmosphere (50 psi/25° C.) for 12 h. The catalyst wasfiltered, and the filtrate was concentrated under the reduced pressureto dryness to give the product of Step C (20 g, 93.0%). ¹H NMR (400 MHz,DMSO-d6) δ ppm 6.95-7.10 (m, 2H), 3.86 (s, 3H)

Step D: Methyl2,6-difluoro-3-{[(2-propen-1-yloxy)carbonyl]amino}benzoate

To a solution of methyl 3-amino-2,6-difluorobenzoate (75 g, 401 mmol) inTHF (300 mL), saturated NaHCO₃ (1400 mL) was added. Then 2-propen-1-ylchloridocarbonate (67.0 g, 561 mmol) was added dropwise at 0° C. Themixture was stirred at rt for 2 h. The solution was extracted with EtOAc(500 mL×3). The combined organic layers were washed with water and brinesuccessively, dried over Na₂SO₄, filtered and concentrated under reducedpressure to give the title compound of Step D (92.5 g, 85.6% yield),which was used to the next step directly. ¹H NMR (400 MHz, CDCl₃) δ ppm8.05-8.20 (br, 1H), 6.88-6.95 (m, 1H), 5.86-6.01 (m, 1H), 5.21-5.40 (m,2H), 4.54-4.69 (m, 2H), 3.92 (s, 3H).

Step E: 2-Propen-1-yl{3-[(2-chloro-4-pyrimidinyl)acetyl]-2,4-difluorophenyl}carbamate

Following a procedure analogous to the procedure described inIntermediate 11 using methyl2,6-difluoro-3-{[(2-propen-1-yloxy)carbonyl]amino}benzoate (80 g, 295mmol) and 2-chloro-4-methylpyrimidine (41.6 g, 324 mmol) the titlecompound of Step E was obtained (65 g, 60.2% yield). ¹H NMR (400 MHz,DMSO-d6) δ ppm 9.49-9.60 (m, 1H), 8.72-8.77 (m, 0.3H), 8.58-8.64 (m,0.6H), 7.57-7.83 (m, 2H), 7.15-7.25 (m, 1H), 5.89-6.01 (m, 1H),5.75-5.82 (m, 0.6H), 5.20-5.40 (m, 2H), 4.55-4.62 (m, 2H), m/z (ES+):368 [M+H]⁺.

Step F: 2-Propen-1-yl{3-[5-(2-chloro-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]-2,4-difluorophenyl}carbamate

Following a procedure analogous to the procedure described inIntermediate 6 using 2-propen-1-yl{3-[(2-chloro-4-pyrimidinyl)acetyl]-2,4-difluorophenyl}carbamate (4.0 g,10.88 mmol), NBS (2.033 g, 11.42 mmol) and 4-morpholinecarbothioamide(1.749 g, 11.97 mmol) the title compound of Step F was obtained as ayellow solid (5.11 g, 95% yield). ¹H NMR (400 MHz, DMSO-d6) δ ppm 9.56(br. s., 1H), 8.41-8.51 (m, 1H), 7.83 (d, J=5.9 Hz, 1H), 7.27 (t, J=8.7Hz, 1H), 6.76 (d, J=5.3 Hz, 1H), 5.88-6.03 (m, 1H), 5.34 (d, J=17.2 Hz,1H), 5.22 (d, J=10.1 Hz, 1H), 4.61 (d, J=5.1 Hz, 2H), 3.70-3.76 (m, 4H),3.57 (d, J=4.4 Hz, 4H). MS (ESI): 493 [M+H]⁺.

Step G:3-[5-(2-Chloro-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]-2,4-difluoroaniline

Following a procedure analogous to the procedure described inIntermediate 13 using 2-propen-1-yl{3-[5-(2-chloro-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]-2,4-difluorophenyl}carbamate(5.11 g, 10.35 mmol) the title compound of Step G was obtained as alight yellow solid (2.71 g 64% yield). ¹H NMR (400 MHz, DMSO-d6) δ ppm8.44 (d, J=5.5 Hz, 1H), 6.90-7.00 (m, 2H), 6.73 (d, J=5.5 Hz, 1H), 5.23(s, 2H), 3.71-3.76 (m, 4H), 3.54-3.60 (m, 4H). MS (ESI): 409 [M+H]⁺.

Step H:N-{3-[5-(2-Chloro-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]-2,4-difluorophenyl}-2,5-difluorobenzenesulfonamide

Following a procedure analogous to the procedure described inIntermediate 14 using3-[5-(2-chloro-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]-2,4-difluoroaniline(900 mg, 2.196 mmol) and 2,5-difluorobenzenesulfonyl chloride (0.355 mL,2.64 mmol) the title compound of Step H was obtained as a light yellowsolid (774 mg, 60% yield). ¹H NMR (400 MHz, DMSO-d6) δ ppm 8.41 (d,J=5.5 Hz, 1H), 7.48-7.57 (m, 4H), 7.29 (t, J=8.8 Hz, 1H), 6.57 (d, J=5.5Hz, 1H), 3.70-3.74 (m, 4H), 3.52-3.55 (m, 4H). MS (ESI): 585 [M+H]⁺.

Step I:N-{3-[5-(2-Amino-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]-2,4-difluorophenyl}-2,5-difluorobenzenesulfonamide

Following a procedure analogous to the procedure described in Example 21usingN-{3-[5-(2-chloro-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]-2,4-difluorophenyl}-2,5-difluorobenzenesulfonamide(150 mg, 0.256 mmol) and NH₄OH (2.5 mL, 17.97 mmol) heated in amicrowave reactor at 130° C. for 30 min the title compound was obtainedas a light yellow solid (127 mg, 83% yield). ¹H NMR (400 MHz, DMSO-d6) δppm 10.74 (br. s., 1H), 7.90 (d, J=5.3 Hz, 1H), 7.46-7.58 (m, 4H), 7.25(t, J=8.8 Hz, 1H), 6.62 (br. s., 2H), 5.61 (d, J=5.1 Hz, 1H), 3.69-3.74(m, 4H), 3.42-3.47 (m, 4H). MS (ESI): 566 [M+H]⁺.

Example 106N-{3-[5-(2-Amino-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]-2,4-difluorophenyl}-2,6-difluorobenzenesulfonamide

Step A:N-{3-[5-(2-Chloro-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]-2,4-difluorophenyl}-2,6-difluorobenzenesulfonamide

Following a procedure analogous to the procedure described inIntermediate 14 using3-[5-(2-chloro-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]-2,4-difluoroaniline(900 mg, 2.196 mmol) and 2,6-difluorobenzenesulfonyl chloride (0.357 mL,2.64 mmol) the title compound of Step A was obtained as a light yellowsolid (857 mg, 66% yield). ¹H NMR (400 MHz, DMSO-d6) δ ppm 10.89 (s,1H), 8.40 (d, J=5.5 Hz, 1H), 7.64-7.72 (m, 1H), 7.49-7.56 (m, 1H),7.21-7.32 (m, 3H), 6.55 (d, J=5.3 Hz, 1H), 3.70-3.74 (m, 4H), 3.52-3.55(m, 4H). MS (ESI): 585 [M+H]⁺.

Step B:N-{3-[5-(2-Amino-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]-2,4-difluorophenyl}-2,6-difluorobenzenesulfonamide

Following a procedure analogous to the procedure described in Example 21usingN-{3-[5-(2-chloro-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]-2,4-difluorophenyl}-2,6-difluorobenzenesulfonamide(150 mg, 0.256 mmol) and NH₄OH (2.5 mL, 17.97 mmol) heated in themicrowave at 130° C. for 15 min the title compound was obtained as alight yellow solid (124 mg, 81%). ¹H NMR (400 MHz, DMSO-d6) δ ppm 10.85(br. s., 1H), 7.90 (d, J=5.3 Hz, 1H), 7.60-7.74 (m, 1H), 7.49 (td,J=8.7, 6.1 Hz, 1H), 7.16-7.34 (m, 3H), 6.62 (s, 2H), 5.63 (d, J=5.3 Hz,1H), 3.67-3.74 (m, 4H), 3.40-3.48 (m, 4H). MS (ESI): 566 [M+H]⁺.

Example 107N-{3-[5-(2-amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2,4-difluorophenyl}-2,6-difluorobenzenesulfonamide

Step A: 2-Propen-1-yl{3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2,4-difluorophenyl}carbamate

Following a procedure analogous to the procedure described inIntermediate 6 using 2-propen-1-yl{3-[(2-chloro-4-pyrimidinyl)acetyl]-2,4-difluorophenyl}carbamate (10 g,27.2 mmol) NBS (5.08 g, 28.6 mmol) and 2,2-dimethylpropanethioamide(3.51 g, 29.9 mmol) the title compound of Step A was obtained (2.15 g,17% yield). ¹H NMR (400 MHz, DMSO-d6) δ ppm 9.55 (br. s., 1H), 8.67 (d,J=5.3 Hz, 1H), 7.83 (d, J=6.0 Hz, 1H), 7.27 (t, J=8.9 Hz, 1H), 7.16 (d,J=5.3 Hz, 1H), 5.89-6.01 (m, 1H), 5.34 (d, J=17.2 Hz, 1H), 5.22 (d,J=10.4 Hz, 1H), 4.60 (d, J=5.3 Hz, 2H), 1.45 (s, 9H); MS (ESI): 464[M+H]⁺.

Step B:{3-[5-(2-Chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2,4-difluorophenyl}amine

Following a procedure analogous to the procedure described inIntermediate 13 using 2-propen-1-yl{3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2,4-difluorophenyl}carbamate(2.962 g, 6.37 mmol) (from composite batches prepared as describedabove) the title compound of Step B was obtained (1.96 g, 81% yield). ¹HNMR (400 MHz, DMSO-d6) δ ppm 8.67 (d, J=5.3 Hz, 1H), 7.09 (d, J=5.3 Hz,1H), 6.88-7.02 (m, 2H), 5.23 (s, 2H), 1.45 (s, 9H); MS (ESI): 380[M+H]⁺.

Step C:N-{3-[5-(2-Chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2,4-difluorophenyl}-2,6-difluorobenzenesulfonamide

Following a procedure analogous to the procedure described inIntermediate 14 using{3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2,4-difluorophenyl}amine(500 mg, 1.313 mmol) and 2,6-difluorobenzenesulfonyl chloride (0.214 mL,1.575 mmol) the title compound of Step C was obtained as a light yellowsolid (653 mg, 89% yield). ¹H NMR (400 MHz, DMSO-d6) δ ppm 10.88 (s,1H), 8.63 (d, J=5.3 Hz, 1H), 7.63-7.74 (m, 1H), 7.52 (td, J=8.7, 6.0 Hz,1H), 7.17-7.35 (m, 3H), 6.99 (d, J=5.3 Hz, 1H), 1.42 (s, 9H). MS (ESI):556 [M+H]⁺.

Step D:N-{3-[5-(2-Amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2,4-difluorophenyl}-2,6-difluorobenzenesulfonamide

Following a procedure analogous to the procedure described in Example 21usingN-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2,4-difluorophenyl}-2,6-difluorobenzenesulfonamide(150 mg, 0.269 mmol) and NH₄OH (2.5 mL, 17.97 mmol) heated in themicrowave at 130° C. for 15 min the title compound was obtained as alight yellow solid (135 mg, 89% yield). ¹H NMR (400 MHz, DMSO-d6) δ ppm10.86 (s, 1H), 8.05 (d, J=5.1 Hz, 1H), 7.62-7.73 (m, 1H), 7.44-7.59 (m,1H), 7.17-7.34 (m, 3H), 6.79 (br. s., 2H), 5.83 (d, J=5.1 Hz, 1H), 1.39(s, 9H). MS (ESI): 537 [M+H]⁺.

Example 108N-{3-[5-(2-Amino-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]-4-fluorophenyl}-2,6-difluorobenzenesulfonamide

Step A: Methyl 5-amino-2-fluorobenzoate

To a solution of 5-amino-2-fluorobenzoic acid (89.6 g, 577 mmol) in MeOH(1000 mL) was added sulfurous dichloride (82.4 g, 692 mmol) dropwise at0° C. Then the mixture was heated to reflux for overnight. The solventwas removed. The residue was diluted with EtOAc (1 L). Then the pH wasadjusted to around 9 by progressively adding saturated NaHCO₃. Theorganic layer was separated. The aqueous layer was extracted with EtOAc(500 L×3). The combined organic layers were washed with water and brinesuccessively, dried over Na₂SO₄, filtered and concentrated under reducedpressure to give the title compound of step A (79.8 g, 81.8% yield). ¹HNMR (400 MHz, CDCl₃) δ ppm 7.16-7.20 (m, 1H), 6.90-6.98 (m, 1H),6.75-6.82 (m, 1H), 3.89 (s, 3H), 3.51-3.70 (br, 2H).

Step B: Methyl 5-{[(2,6-difluorophenyl)sulfonyl]amino}-2-fluorobenzoate

Following a procedure analogous to the procedure described in Example 5,Step A using methyl 5-amino-2-fluorobenzoate (10 g, 59.2 mmol) and2,6-difluorobenzene-1-sulfonyl chloride (13.2 g, 62.2 mmol) the titlecompound of Step B was obtained (21 g, 100% yield). ¹H NMR (400 MHz,CDCl₃) δ ppm 7.58-7.60 (m, 1H), 7.38-7.48 (m, 2H), 7.10-7.15 (br, 1H),6.89-6.97 (m, 2H), 6.97-7.06 (m, 1H), 3.85 (s, 3H).

Step C:N-{3-[5-(2-Chloro-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]-4-fluorophenyl}-2,6-difluorobenzenesulfonamide

To a solution of methyl5-{[(2,6-difluorophenyl)sulfonyl]amino}-2-fluorobenzoate (21 g, 60.8mmol) in dry THF (250 mL) at −10° C., LIHMDS (1M in THF, 213 mmol, 213mL) was added dropwise and the solution was allowed to stir for 1 h at0° C. A solution of pyrimidine chloride (9.3 g, 73 mmol) in THF (50 mL)was then added dropwise to the solution of ester and base at 0° C. over20 min. The solution was allowed to stir 1 h at rt. TLC showed thereaction was complete. The reaction was quenched by addition of thesaturated aqueous NH₄Cl (200 mL) at 0° C. The reaction mixture wasextracted with EtOAc (100 mL×3). The combined organic layers were washedwith water and brine successively, dried over Na₂SO₄, filtered andconcentrated under reduced pressure to give the crude product, which waspurified by flush column on silica gel, rinsing with DCM. This solutionwas concentrated to obtain a solid. The orange solid was triturated witha small amount of EtOAc and filtered, rinsing with diethyl ether to giveN-(3-(2-(2-chloropyrimidin-4-yl)acetyl)-4-fluorophenyl)-2,6-difluorobenzenesulfonamide(13 g, 50.5%).N-(3-(2-(2-chloropyrimidin-4-yl)acetyl)-4-fluorophenyl)-2,6-difluorobenzenesulfonamide(13 g) was diluted in DMA (150 mL). NBS (5.5 g, 30.7 mmol) was added andthe reaction mixture was stirred at rt for 1 h. Then2-methylpropanethioamide (4.8 g, 33.8 mmol) was added at 0° C. Themixture was stirred at rt for 2 h. The mixture was poured into water andextracted with EtOAc (500 mL×3). The combined organic layers were washedwith water and brine successively, dried over Na₂SO₄, filtered andconcentrated under reduced pressure to give the crude product, which waspurified by column chromatography on silica gel (DCM:petroleum ether2:1) to afford the title compound of Step C (7.5 g, 22% yield over 2steps). ¹H NMR (400 MHz, CDCl₃) δ ppm 8.11 (d, J=5.5 Hz, 1H), 7.48-7.56(m, 1H), 7.40-7.48 (br, 1H), 7.26-7.38 (m, 2H), 7.07-7.14 (m, 1H),6.92-7.04 (m, 2H), 6.51 (d, J=5.5 Hz, 1H), 3.80-3.88 (m, 4H), 3.58-3.65(m, 4H), m/z (ES+): 468 [M+H]⁺.

Step D:N-{3-[5-(2-Amino-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]-4-fluorophenyl}-2,6-difluorobenzenesulfonamide

Following a procedure analogous to the procedure described in Example 21usingN-{3-[5-(2-chloro-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]-4-fluorophenyl}-2,6-difluorobenzenesulfonamide(150 mg, 0.264 mmol) and NH₄OH (3 mL) heated at 120° C. in a microwavereactor for 15 min, the title compound was obtained as a yellow solid(67 mg, 0.122 mmol, 46.2% yield). ¹H NMR (400 MHz, DMSO-d6) δ ppm 10.99(s, 1H), 7.78 (d, J=5.3 Hz, 1H), 7.59-7.75 (m, 1H), 7.18-7.30 (m, 4H),7.15 (d, J=5.8 Hz, 1H), 6.57 (s, 2H), 5.59 (d, J=5.2 Hz, 1H), 3.64-3.77(m, 4H), 3.40-3.47 (m, 4H). m/z (ES+): 549 [M+H]+.

Example 109N-{3-[5-(2-Chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-4-fluorophenyl}-2,6-difluorobenzenesulfonamide

Step A: Methyl 2-fluoro-5-{[(2-propen-1-yloxy)carbonyl]amino}benzoate

To a solution of methyl 5-amino-2-fluorobenzoate (67 g, 396 mmol) in THF(400 mL), saturated NaHCO₃ (1200 mL) was added. Then 2-propen-1-ylchloridocarbonate (57 g, 476 mmol,) was added dropwise at 0° C. Themixture was stirred at rt for 2 h. The solution was extracted with EtOAc(500 mL×3). The combined organic layers were washed with water and brinesuccessively, dried over Na₂SO₄, filtered and concentrated under reducedpressure to give the title compound of Step A (102 g, 100% yield), whichwas used to the next step directly. ¹H NMR (400 MHz, CD₃Cl) δ ppm7.75-7.78 (m, 1H), 7.57-7.67 (m, 1H), 6.98-7.07 (m, 1H), 6.67-6.70 (m,5.83-5.97), 5.83-5.97 (m, 1H), 5.17-7.35 (m, 2H), 4.60-4.65 (m, 2H),3.85 (s, 1H).

Step B: 2-Propen-1-yl{3-[(2-chloro-4-pyrimidinyl)acetyl]-4-fluorophenyl}carbamate

Using multiple interations of a procedure analogous to the proceduredescribed in Intermediate 11 using methyl2-fluoro-5-{[(2-propen-1-yloxy)carbonyl]amino}benzoate (104 g, 411 mmol)and 2-chloro-4-methylpyrimidine (59 g, 493 mmol), the title compound ofStep B was obtained (100 g, 69.9% yield). ¹H NMR (400 MHz, CDCl₃) δ ppm13.67-13.75 (br, 1H), 8.50-8.53 (m, 0.3H), 8.31-8.38 (m, 1H), 7.50-7.82(m, 2.6H), 6.56-7.20 (m, 3.5H), 6.20-6.25 (m, 1H), 5.82-6.01 (1.3H),5.20-5.40 (m, 2.6H), 4.50-4.61 (m, 2.6H), 4.31-4.41 (m, 0.9H).

Step C: 2-Propen-1-yl{3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-4-fluorophenyl}carbamate

Following a procedure analogous to the procedure described inIntermediate 6 using 2-propen-1-yl{3-[(2-chloro-4-pyrimidinyl)acetyl]-4-fluorophenyl}carbamate (20 g, 57.3mmol), NBS (10.2 g, 57.3 mmol) and 2-methylpropanethioamide (7.4 g, 63mmol) the title compound of Step C was obtained (11 g, 44.9% yield). ¹HNMR (400 MHz, DMSO-d6) δ ppm 9.90-9.98 (br, 1H), 8.61 (d, J=5.3 Hz, 1H),7.65-7.72 (m, 1H), 7.49-7.54 (m, 1H), 7.21-7.30 (m, 1H), 7.10 (d, J=5.3Hz, 1H), 5.90-6.05 (m, 1H), 5.20-5.40 (m, 2H), 4.58-4.63 (m, 2H), 1.47(s, 9H).

Step D:3-[5-(2-Chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-4-fluoroaniline

To a solution of 2-propen-1-yl{3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-4-fluorophenyl}carbamate(11 g, 24.6 mmol) in DCM (200 mL), HOAc (3.6 g, 59.2 mmol), Pd(PPh₃)₂Cl₂(345 mg, 0.5 mmol) were added. Then tri-n-butyl tin hydride (8.6 g, 29.6mmol) was added dropwise to the mixture at 0° C. The mixture was stirredat rt for 30 min. The reaction was quenched by adding saturated NaHCO₃(100 mL) slowly. The two layers were separated. The aqueous layer wasextracted with DCM (100 mL×2). The combined organic layers were washedwith water and brine successively, dried over Na₂SO₄, filtered andconcentrated under reduced pressure and washed with petroleum ether (200mL) to afford the crude product,3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-4-fluoroaniline(7.62 g, 85.3% yield), 7.4 g of which was used directly in the nextstep.

Step E:N-{3-[5-(2-Chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-4-fluorophenyl}-2,6-difluorobenzenesulfonamide

To a solution of3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-4-fluoroaniline(7.4 g, 20.4 mmol) in DCM (200 mL) was added pyridine (4.85 g, 61.3mmol) and cooled to 0° C. 2,6-Difluorobenzene-1-sulfonyl chloride (4.76g, 22.5 mmol) in DCM (10 mL) was added dropwise to the mixture. Thereaction was stirred at rt overnight. Then the reaction was washed withwater (200 mL), and extracted with DCM (2×100 mL). The organic layer waswashed with brine, dried over anhydrous Na₂SO₄, filtrated andconcentrated under reduced pressure to give the crude product, which waspurified by column chromatography on silica gel (petroleum ether:EtOAc5:1) to afford the title compound of Step E (2.3 g, 7.2% yield). ¹H NMR(400 MHz, DMSO-d6) δ ppm 8.56 (d, J=5.3 Hz, 1H), 7.62-7.75 (m, 1H),7.20-7.32 (m, 5H), 6.92 (d, J=5.3 Hz, 1H), 1.40 (s, 9H). m/z (ES+): 539[M+H]⁺.

Step F:N-{3-[5-(2-Chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-4-fluorophenyl}-2,6-difluorobenzenesulfonamide

Following a procedure analogous to the procedure described in Example 21usingN-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-4-fluorophenyl}-2,6-difluorobenzenesulfonamide(150 mg, 0.278 mmol) and NH₄OH (3 mL) heated in a microwave reactor at120° C. for 20 min the title compound was obtained as an off-white solid(135 mg, 0.260 mmol, 93% yield). ¹H NMR (400 MHz, DMSO-d6) δ ppm 11.01(br. s., 1H), 7.93 (d, J=5.1 Hz, 1H), 7.54-7.76 (m, 1H), 7.10-7.30 (m,5H), 6.71 (s, 2H), 5.81 (d, J=5.0 Hz, 1H), 1.36 (s, 9H). m/z (ES+): 520[M+H]+.

Example 110N-{3-[5-(2-Amino-4-pyrimidinyl)-2-(1-pyrrolidinyl)-1,3-oxazol-4-yl]phenyl}-2,6-difluorobenzenesulfonamide

Step A:N-{3-[5-(2-Chloro-4-pyrimidinyl)-2-(1-pyrrolidinyl)-1,3-oxazol-4-yl]phenyl}-2,6-difluorobenzenesulfonamide

Following a procedure analogous to the procedure described inIntermediate 6 usingN-{3-[(Z)-2-(2-chloro-4-pyrimidinyl)-1-hydroxyethenyl]phenyl}-2,6-difluorobenzenesulfonamide(2.0 g, 4.72 mmol, NBS (0.924 g, 5.19 mmol) and 1-pyrrolidinecarboxamide(1.077 g, 9.44 mmol) heated to 90° C. for 24 h the title compound ofStep A was obtained as an orange solid (0.980 g). MS-ESI m/z 518 (M+H).

Step B:N-{3-[5-(2-amino-4-pyrimidinyl)-2-(1-pyrrolidinyl)-1,3-oxazol-4-yl]phenyl}-2,6-difluorobenzenesulfonamide

Following a procedure analogous to the procedure described in Example 21using-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1-pyrrolidinyl)-1,3-oxazol-4-yl]phenyl}-2,6-difluorobenzenesulfonamide(0.100 g, 0.193 mmol) and NH₄OH (2 mL) heated in a microwave reactor at120° C. for 10 min the title compound was obtained as a yellow solid(0.010 g). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.92 (s, 1H), 8.14 (d, J=5.2Hz, 1H), 7.86-8.02 (m, 2H), 7.59-7.70 (m, 1H), 7.31 (t, J=7.6 Hz, 1H),7.10-7.26 (m, 3H), 6.50-6.60 (m, 3H), 3.50 (t, J=6.4 Hz, 4H), 1.88-1.99(m, 4H). MS-ESI m/z 499 (M+H).

Example 1112,6-Difluoro-N-{3-[5-{2-[(2-methylpropyl)amino]-4-pyrimidinyl}-2-(1-pyrrolidinyl)-1,3-oxazol-4-yl]phenyl}benzenesulfonamide

To a 8 mL vialN-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1-pyrrolidinyl)-1,3-oxazol-4-yl]phenyl}-2,6-difluorobenzenesulfonamide(0.100 g, 0.193 mmol) was taken up in isobutylamine (2 mL) to give ayellow solution. Vial was capped and heated to 45° C. for 2 h. Thesolvent was removed and residue was purified via Gilson Acidic HPLC (10to 90% gradient, Acetonitrile/H₂O+TFA; C18 column). Desired fractionswere diluted with EtOAc and washed with saturated aq. NaHCO₃, dried overNa₂SO₄ and solvent removed to give title compound as a yellow solid(0.074 g). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.93 (s, 1H), 8.18 (d, J=5.1Hz, 1H), 7.81 (br. s., 1H), 7.59-7.73 (m, 2H), 7.24 (t, J=9.1 Hz, 3H),7.14 (d, J=7.9 Hz, 1H), 6.97 (t, J=5.7 Hz, 1H), 6.57 (d, J=1.6 Hz, 1H),3.52 (t, J=6.3 Hz, 4H), 2.76-2.90 (m, 1H), 1.92-2.01 (m, 4H), 0.55-0.94(m, 6H). MS-ESI m/z 555 (M+H).

Example 112N-{3-[5-(2-Amino-4-pyrimidinyl)-2-(dimethylamino)-1,3-thiazol-4-yl]phenyl}-2,6-difluorobenzenesulfonamide

Step A:N-{3-[5-(2-Chloro-4-pyrimidinyl)-2-(dimethylamino)-1,3-thiazol-4-yl]phenyl}-2,6-difluorobenzenesulfonamide

ToN-{3-[(Z)-2-(2-chloro-4-pyrimidinyl)-1-hydroxyethenyl]phenyl}-2,6-difluorobenzenesulfonamide(2.0 g, 4.72 mmol) in 25 mL DMA was added NBS (0.88 g, 4.95 mmol). Themixture stirred at rt for 30 min. N,N-Dimethylthiourea (0.6 g, 5.66mmol) was added and the mixture heated to 40° C. overnight. The mixturewas poured into 300 mL ice water and the crude product was collected byfiltration. The crude product was then purified by flash chromatographyto give the title compound of Step A (0.6 g, 1.18 mmol, 25% yield). ¹HNMR (400 MHz, DMSO-d6) δ ppm 11.09 (s, 1H), 8.14 (d, J=5.5 Hz, 1H), 7.68(s, 2H), 7.37 (d, J=7.9 Hz, 1H), 7.22 (ddd, J=17.3, 8.5, 8.2 Hz, 5H),6.47 (d, J=5.5 Hz, 1H), 3.12 (s, 6H).

Step B:N-{3-[5-(2-Amino-4-pyrimidinyl)-2-(dimethylamino)-1,3-thiazol-4-yl]phenyl}-2,6-difluorobenzenesulfonamide

N-{3-[5-(2-Chloro-4-pyrimidinyl)-2-(dimethylamino)-1,3-thiazol-4-yl]phenyl}-2,6-difluorobenzenesulfonamide(0.1 g, 0.2 mmol) was taken up in 2 mL 30% NH₄OH (aq) and heated to 140°C. for 20 min in a microwave reactor. The solvent was removed underreduced pressure and the residue taken up in EtOAc and washed with 2 mLof 0.1N HCl (aq). The organic layer was dried over Na₂SO₄ and evaporatedonto silica gel. Purification by flash chromatography (0 to 40%EtOAC/DCM) afforded the title compound (30 mg, 0.061 mmol, 31% yield) asa yellow solid. ¹H NMR (400 MHz, DMSO-d6) δ ppm 10.98 (s, 1H), 7.59-7.70(m, 2H), 7.26-7.35 (m, 1H), 7.15-7.25 (m, 4H), 7.09 (d, J=7.5 Hz, 1H),6.48 (s, 2H), 5.68 (d, J=5.3 Hz, 1H), 3.03 (s, 6H)). MS (ESI): 489[M+H]⁺.

Example 113N-[3-(2-(Dimethylamino)-5-{2-[(2-methylpropyl)amino]-4-pyrimidinyl}-1,3-thiazol-4-yl)phenyl]-2,6-difluorobenzenesulfonamide

N-{3-[5-(2-Chloro-4-pyrimidinyl)-2-(dimethylamino)-1,3-thiazol-4-yl]phenyl}-2,6-difluorobenzenesulfonamide(0.1 g, 0.2 mmol) was taken up in 2 mL isobutylamine and heated to 35°C. overnight. The solvent was removed under reduce pressure and theresidue taken up in EtOAc and washed with 2 mL of 0.1N HCl (aq). Theorganic layer was dried over Na₂SO₄ and evaporated to afforded the titlecompound (36 mg, 0.066 mmol, 33.6% yield) as a yellow solid. ¹H NMR (400MHz, DMSO-d6) δ ppm 11.01 (s, 1H), 7.74 (d, J=5.3 Hz, 1H), 7.67 (ddd,J=14.6, 8.4, 6.1 Hz, 1H), 7.28-7.35 (m, 1H), 7.18-7.28 (m, 4H), 7.12 (d,J=7.7 Hz, 1H), 7.07 (t, J=5.5 Hz, 1H), 5.68 (s, 1H), 3.06 (s, 6H), 3.02(t, J=6.3 Hz, 2H), 1.82 (dt, J=13.4, 6.7 Hz, 1H), 0.86 (d, J=6.8 Hz,6H). MS (ESI): 545 [M+H]⁺.

Example 114N-{3-[5-(2-Amino-4-pyrimidinyl)-1,3-thiazol-4-yl]phenyl}-2,6-difluorobenzenesulfonamide

Step A:N-{3-[2-Amino-5-(2-chloro-4-pyrimidinyl)-1,3-thiazol-4-yl]phenyl}-2,6-difluorobenzenesulfonamide

ToN-{3-[(Z)-2-(2-chloro-4-pyrimidinyl)-1-hydroxyethenyl]phenyl}-2,6-difluorobenzenesulfonamide(2.0 g, 4.72 mmol) in 40 mL of DMA was added NBS (0.88 g, 4.95 mmol).The mixture stirred at room temperature for 30 min. Thiourea (0.36 g,4.72 mmol) as added and the mixture heated to 80° C. for 1 h. Themixture was poured into 300 mL of ice water and the product wascollected by filtration. The crude product was then purified by flashchromatography to give the title compound of Step A (1.61 g, 3.35 mmol,67.5% yield). ¹H NMR (400 MHz, DMSO-d6) δ ppm 11.05 (s, 1H), 8.16 (d,J=5.5 Hz, 1H), 7.94 (s, 2H), 7.64-7.75 (m, 1H), 7.37 (d, J=7.8 Hz, 1H),7.16-7.29 (m, 5H), 6.52 (d, J=5.6 Hz, 1H).

Step B:N-{3-[5-(2-Chloro-4-pyrimidinyl)-1,3-thiazol-4-yl]phenyl}-2,6-difluorobenzenesulfonamide

ToN-{3-[2-amino-5-(2-chloro-4-pyrimidinyl)-1,3-thiazol-4-yl]phenyl}-2,6-difluorobenzenesulfonamide (0.8 g, 1.67 mmol) in 10 mL THF was added t-butylnitrite(0.4 mL, 4 mmol) by syringe. The mixture stirred at rt for 1 h. Moret-butylnitrite (0.2 mL, 2 mmol) was added and the mixture heated to 80°C. for 1 h. The mixture was cooled, diluted with 100 mL EtOAc, washedwith 20 mL water, filtered through Whatman 1 PS (phase separating) paperand concentrated under vacuum. The crude product was then purified byflash chromatography to give the title compound of Step B (0.53 g, 1.14mmol, 65% yield). ¹H NMR (400 MHz, DMSO-d6) δ ppm 11.07 (s, 1H), 9.37(s, 1H), 8.55 (d, J=5.3 Hz, 1H), 7.65-7.75 (m, 1H), 7.40 (t, J=8.0 Hz,1H), 7.23-7.32 (m, 5H), 7.03 (d, J=5.3 Hz, 1H).

Step C:N-{3-[5-(2-Amino-4-pyrimidinyl)-1,3-thiazol-4-yl]phenyl}-2,6-difluorobenzenesulfonamide

N-{3-[5-(2-Chloro-4-pyrimidinyl)-1,3-thiazol-4-yl]phenyl}-2,6-difluorobenzenesulfonamide(0.1 g, 0.2 mmol) was taken up in 2 mL NH₄OH and heated to 140° C. for20 min in a microwave reactor. The solvent was removed under reducedpressure and the residue was taken up in EtOAc and washed with 2 mL of0.1N HCl (aq). The organic layer was dried over Na₂SO₄ and evaporatedonto silica gel. Purification by ISCO chromatography (0 to 50% EtOAC inDCM) afforded the title compound (62 mg, 0.139 mmol, 64.7% yield) as ayellow solid. ¹H NMR (400 MHz, DMSO-d6) δ ppm 11.00 (s, 1H), 9.16 (s,1H), 7.94 (d, J=5.1 Hz, 1H), 7.59-7.69 (m, 1H), 7.32 (t, J=7.9 Hz, 1H),7.16-7.27 (m, 5H), 6.78 (s, 2H), 5.99 (d, J=5.3 Hz, 1H). MS (ESI): 446[M+H]⁺.

Example 1152,6-Difluoro-N-[3-(5-{2-[(2-methylpropyl)amino]-4-pyrimidinyl}-1,3-thiazol-4-yl)phenyl]benzenesulfonamide

N-{3-[5-(2-Chloro-4-pyrimidinyl)-1,3-thiazol-4-yl]phenyl}-2,6-difluorobenzenesulfonamide(0.1 g, 0.2 mmol) was taken up in 2 mL isobutylamine and heated to 35°C. overnight. The solvent was removed in vacuo and the residue taken upin EtOAc and washed with 2 mL of 0.1N HCl (aq). The organic layer wasdried over Na₂SO₄ and evaporated to afford the title compound (65 mg,0.130 mmol), 60.2% yield) as a yellow solid. ¹H NMR (400 MHz, DMSO-d6) δppm 11.00 (s, 1H), 9.15 (s, 1H), 7.98 (d, J=5.1 Hz, 1H), 7.60-7.69 (m,1H), 7.37 (t, J=5.9 Hz, 1H), 7.31 (t, J=7.9 Hz, 1H), 7.26 (s, 1H),7.15-7.24 (m, 4H), 5.93-6.05 (m, 1H), 2.95-3.06 (m, 2H), 0.82 (d, J=6.6Hz, 6H). MS (ESI): 501 [M+H]⁺.

Example 116N-{3-[5-(2-Amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]phenyl}-2,5-difluorobenzenesulfonamide

A suspension ofN-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]phenyl}-2,5-difluorobenzenesulfonamide(150 mg, 0.288 mmol) and 2M ammonia in isopropanol (8.0 mL, 16.0 mmol)was heated in a sealed tube at 100° C. overnight. The reaction mixturewas evaporated onto silica gel and chromatographed (10-100% 1:9MeOH:EtOAc in DCM). The title compound was recovered as a beige solid(38 mg, 25% yield). ¹H NMR (400 MHz, DMSO-d6) δ ppm 10.89 (s, 1H), 7.95(d, J=5.1 Hz, 1H), 7.41-7.68 (m, 3H), 7.31 (t, J=7.9 Hz, 1H), 7.23 (s,1H), 7.17 (d, J=7.9 Hz, 2H), 6.74 (s, 2H), 6.01 (d, J=5.1 Hz, 1H), 1.38(s, 9H). MS (ESI): 502.1 [M+H]⁺.

Examples 117-217

The following compounds were prepared using method analogous to thosedescribed above.

Ex Structure m/z [M + H]⁺ ¹H NMR 117

518 [ES+] ¹H NMR (400 MHz, CDCl₃) δ ppm 7.95 (d, J = 5.2 Hz, 1 H)7.47-7.66 (m, 2 H) 7.04-7.44 (m, 5 H) 6.06 (d, J = 5.2 Hz, 1 H)4.92-5.08 (m, 2 H) 3.82 (quin, J = 8.4 Hz, 1 H) 2.25-2.55 (m, 4 H)1.87-2.16 (m, 2 H) 118

518 [ES+] ¹H NMR (400 MHz, CDCl₃) δ ppm 7.95 (d, J = 5.3 Hz, 1 H) 7.70(t, J = 7.2 Hz, 1 H) 7.37-7.51 (m, 2 H) 7.27 (t, J = 7.1 Hz, 1 H) 7.18(t, J = 8.0 Hz, 1 H) 6.94 (t, J = 8.9 Hz, 2 H) 6.09 (d, J = 5.1 Hz, 1 H)4.99 (br. s., 2 H) 3.82 (quin, J = 8.6 Hz, 1 H) 2.26-2.55 (m, 1 H)1.86-2.14 (m, 2 H) 119

520 [ES+] ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.87 (s, 1 H) 8.04 (d, J =4.4 Hz, 1 H) 7.61-7.74 (m, 1 H) 7.29-7.47 (m, 2 H) 7.10-7.30 (m, 4 H)6.14 (br. s., 1 H) 3.17-3.28 (m, 1 H) 2.69 (br. s., 3 H) 1.32 (d, J =6.8 Hz, 6 H) 120

548 [ES+] ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.78 (s, 1 H) 8.07 (d, J =5.3 Hz, 1 H) 7.71 (br. s., 1 H) 7.42-7.62 (m, 3 H) 7.32-7.42 (m, 2 H)7.25 (t, J = 9.2 Hz, 1 H) 6.25 (br. s., 1 H) 3.27 (quin, J = 6.9 Hz, 1H) 3.16 (br. s., 2 H) 1.38-1.58 (m, 2 H) 1.32 (d, J = 7.0 Hz, 6 H) 0.83(t, J = 7.2 Hz, 3 H) 121

562 [ES+] ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.78 (s, 1 H) 8.07 (d, J =4.4 Hz, 1 H) 7.76 (br. s., 1 H) 7.42-7.62 (m, 3 H) 7.32-7.42 (m, 2 H)7.25 (t, J = 9.2 Hz, 1 H) 6.26 (br. s., 1 H) 3.27 (quin, J = 6.9 Hz, 1H) 3.02 (br. s., 2 H) 1.79 (br. s., 1 H) 1.32 (d, J = 6.8 Hz, 6 H) 0.83(d, 6 H) 122

546 [ES+] ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.74 (s, 1 H) 8.08 (d, J =4.8 Hz, 1 H) 7.40-7.62 (m, 5 H) 7.36 (d, J = 7.0 Hz, 2 H) 7.23 (t, J =9.6 Hz, 1 H) 6.21 (d, J = 4.8 Hz, 1 H) 3.18-3.27 (m, 1 H) 2.62 (br. s.,1 H) 1.32 (d, J = 6.8 Hz, 6 H) 0.58 (d, J = 5.3 Hz, 2 H) 0.42 (br. s., 2H) 123

603 [ES+] ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.09 (s, 1 H) 7.96 (d, J = 4.9Hz, 2 H) 7.16-7.37 (m, 4 H) 6.96 (dd, J = 10.1, 9.0 Hz, 1 H) 6.77 (br.s., 1 H) 6.17 (br. s., 1 H) 3.04-3.26 (m, 4 H) 2.67 (br. s., 2 H) 2.53(br. s., 4 H) 1.81-1.99 (m, 2 H) 1.61 (br. s., 2 H) 1.30 (d, J = 6.8 Hz,6 H) 124

689 [ES+] ¹H NMR (400 MHz, CDCl₃) δ ppm 8.01 (d, J = 5.1 Hz, 1 H) 7.68(d, J = 7.0 Hz, 1 H) 7.45 (td, J = 4.8, 2.7 Hz, 1 H) 7.31 (td, J = 5.4,2.4 Hz, 1 H) 7.10-7.28 (m, 3 H) 7.03 (t, J = 9.2 Hz, 1 H) 6.21 (d, J =5.3 Hz, 1 H) 5.08 (d, J = 7.7 Hz, 1 H) 3.83-4.15 (m, 3 H) 3.29 (quin, J= 6.9 Hz, 1 H) 2.84-3.01 (m, 2 H) 2.00 (d, J = 10.3 Hz, 2 H) 1.56 (br.s., 2 H) 1.44 (s, 9 H) 1.41 (d, J = 7.0 Hz, 6 H) 125

589 [ES+] ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.23 (br. s., 1 H) 7.92 (d, J= 4.4 Hz, 1 H) 7.34 (d, J = 7.1 Hz, 1 H) 7.22-7.30 (m, 1 H) 7.19 (dd, J= 8.6, 1.6 Hz, 1 H) 7.11 (t, J = 5.8 Hz, 2 H) 6.89 (dd, J = 11.1, 8.3Hz, 1 H) 6.58 (br. s., 1 H) 6.17 (br. s., 1 H) 3.82 (br. s., 1 H) 3.14-3.25 (m, 2 H) 2.92 (dd, J = 11.5, 10.8 Hz, 2 H) 1.95 (d, J = 11.5 Hz, 2H) 1.49-1.71 (m, 2 H) 1.30 (d, J = 7.0 Hz, 6 H) 126

695 [ES+] ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.04 (d, J = 5.1 Hz, 1 H)7.37-7.63 (m, 4 H) 7.13-7.37 (m, 4 H) 6.05- 6.26 (m, 1 H) 3.33 (q, J =7.1 Hz, 2 H) 3.14-3.25 (m, 1 H) 2.99 (s, 3 H) 2.93 (s, 2 H) 2.62-2.77(m, 2 H) 2.05 (br. s., 2 H) 1.78 (br. s., 2 H) 1.31 (d, J = 6.8 Hz, 6 H)1.04 (t, J = 7.0 Hz, 2H) 127

703 [ES+] ¹H NMR (400 MHz, CDCl₃) δ ppm 8.00 (br. s., 1 H) 7.67 (d, J =5.9 Hz, 1 H) 7.46 (t, J = 7.5 Hz, 1 H) 7.32 (dd, J = 5.2, 3.2 Hz, 1 H)7.10-7.28 (m, J = 9.0, 9.0, 4.8, 4.6 Hz, 1 H) 7.02 (t, J = 9.2 Hz, 1 H)6.20 (d, J = 5.3 Hz, 1 H) 5.35 (br. s., 1 H) 4.11 (br. s., 2 H) 3.24-3.39 (m, 3 H) 2.69 (br. s., 2 H) 1.74 (d, J = 10.8 Hz, 3 H) 1.38-1.48(m, 15 H) 1.05-1.28 (m, 2 H) 128

603 [ES+] ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.83 (s, 1 H) 8.11 (d, J =5.2 Hz, 1 H) 7.44-7.68 (m, 4 H) 7.35- 7.44 (m, 2 H) 7.31 (dd, J = 9.6,8.8 Hz, 1 H) 3.19-3.36 (m, 2 H) 2.82 (br. s., 3 H) 1.80 (br. s., 3 H)1.36 (d, J = 7.0 Hz, 6 H) 1.24-1.34 (m, 1 H) 129

681 [ES+] ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.81 (s, 1 H) 8.10 (d, J =5.0 Hz, 1 H) 7.34-7.68 (m, 6 H) 7.28 (t, J = 9.4 Hz, 1 H) 6.85-6.97 (m,1 H) 3.43-3.63 (m, 2 H) 3.24-3.31 (m, 1 H) 3.03-3.23 (m, 2 H) 2.82 (s, 4H) 2.63 (t, J = 11.8 Hz, 2 H) 1.69 (d, J = 12.0 Hz, 2 H) 1.37 (d, J =1.6 Hz, 6 H) 1.03-1.30 (m, 2 H) 130

681 [ES+] ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.76 (s, 1 H) 8.07 (br. s., 1H) 7.21-7.62 (m, 7 H) 5.69-6.27 (m, 1 H) 3.64-3.98 (m, 1 H) 3.42-3.64(m, 2 H) 2.87 (s, 3 H) 2.59-2.87 (m, 2 H) 1.66-2.04 (m, 2 H) 1.40 (s, 9H) 1.30-1.65 (m, 2 H) 131

617 [ES+] ¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.96 (d, J = 4.8 Hz, 1 H)7.04-7.39 (m, 6 H) 6.97 (t, J = 9.4 Hz, 1 H) 6.77 (br. s., 1 H) 6.18(br. s., 1 H) 3.04-3.67 (m, 3 H) 2.52-2.93 (m, 4 H) 2.16-2.39 (m, 2 H)1.36-1.68 (m, 6 H ) 1.30 (d, 6 H) 132

659 [ES+] ¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.85 (br. s., 1 H) 7.17-7.34(m, 1 H) 7.10 (dd, J = 7.1, 4.8 Hz, 2 H) 6.94-7.05 (m, 1 H) 6.88 (dd, J= 10.9, 8.7 Hz, 1 H) 6.48-6.64 (m, 1 H) 6.01-6.14 (m, 2 H) 4.02 (br. s.,1 H) 3.01-3.23 (m, 1 H) 2.06-2.21 (m, 5 H) 1.69- 1.84 (m, 1 H) 1.65 (dd,J = 12.0, 2.8 Hz, 2 H) 1.28 (d, J = 6.8 Hz, 4 H) 1.18 (t, J = 12.2 Hz, 2H) 0.96-1.10 (m, 14 H) 0.92 (s, 6 H) 133

689 [ES+] ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.75 (s, 1 H) 7.96-8.14 (m, 2H) 7.92 (s, 1 H) 7.40-7.61 (m, 2 H) 7.17-7.40 (m, 2H) 6.16 (br. s., 1 H)3.33-4.18 (m, 3 H) 2.53-3.16 (m, 2 H) 1.75 (s, 4 H) 1.08-1.42 (m, 17 H)134

576 [ES+] ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.82 (s, 1 H) 7.97 (d, J =5.1 Hz, 1 H) 7.56-7.68 (m, 1 H) 7.38 (t, J = 7.0 Hz, 1 H) 7.11-7.33 (m,5 H) 5.65-6.02 (m, 1 H) 2.72-3.16 (m, 2 H) 1.62-1.92 (m, 1 H) 1.36 (s, 9H) 0.82 (d, J = 6.4 Hz, 6 H) 135

563 [ES+] ¹H NMR (400 MHz, CDCl₃) δ ppm 7.42-8.64 (m, 5 H) 7.10-7.42 (m,2 H) 6.84-7.11 (m, 2 H) 6.24 (br. s., 1 H) 4.07 (br. s., 1 H) 3.43 (d, J= 6.2 Hz, 1 H) 1.44 (br. s., 9 H) 1.26 (d, J = 4.8 Hz, 6 H) 136

591 [ES+] ¹H NMR (400 MHz, CDCl₃) δ ppm 8.32 (d, J = 7.4 Hz, 1 H) 7.95(br. s., 1 H) 7.68 (dt, J = 10.0, 3.6 Hz, 1 H) 7.54 (dd, J = 14.2, 2.4Hz, 1 H) 7.44 (d, J = 7.0 Hz, 1 H) 7.17-7.22 (m, 2 H) 6.91-7.05 (m, 2 H)5.89 (d, J = 6.2 Hz, 1 H) 4.08 (quin, J = 6.6 Hz, 1 H) 3.79 (t, J = 4.7Hz, 5 H) 3.62 (t, J = 4.5 Hz, 4 H) 1.27 (d, J = 6.4 Hz, 6 H) 137

586 [ES+] ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.90 (s, 1 H) 8.02 (br. s., 1H) 7.36-7.67 (m, 4 H) 7.29 (t, J = 7.9 Hz, 1 H) 7.05-7.24 (m, 2 H)5.82-6.41 (m, 1 H) 3.62- 3.96 (m, 2 H) 3.09-3.41 (m, 3 H) 1.59-1.85 (m,2 H) 1.39-1.56 (m, 1 H) 1.37 (s, 9 H) 138

604 [ES+] ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.74 (s, 1 H) 8.07 (br. s., 1H) 7.29-7.74 (m, 6 H) 7.24 (t, J = 7.8 Hz, 1 H) 5.67-6.36 (m, 1 H)3.66-3.92 (m, 2 H) 3.10- 3.37 (m, 3 H) 1.68 (br. s., 2 H) 1.38-1.54 (m,2 H) 1.36 (s, 9 H) 139

605 [ES+] ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.84 (br. s, 1 H) 8.24 (br.s., 1 H) 7.63-8.01 (m, 4 H) 7.43-7.63 (m, 2 H) 7.14-7.43 (m, 2 H) 6.07(br. s, 1 H) 3.58- 3.77 (m, 4 H) 3.39-3.56 (m, 2 H) 2.98-3.19 (m, 1 H)2.33-2.50 (m, 4 H) 1.71-1.91 (m, 1 H) 0.87 (d, J = 6.6 Hz, 6 H) 140

663   ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.50 (s, 1 H), 8.11 (d, J = 5.0Hz, 1 H), 7.58-7.67 (m, 1 H), 7.47- 7.57 (m, 2 H), 7.22-7.42 (m, 3 H),7.01 (d, J = 6.9 Hz, 1 H), 6.11-6.27 (m, 1 H), 3.53-4.01 (m, 4 H), 3.26-3.35 (m, 1 H), 3.09 (dt, J = 3.3, 1.6 Hz, 1 H), 2.92 (s, 3 H), 1.92 (d,J = 10.6 Hz, 4 H), 1.19-1.42 (m, 8 H). 141

681   ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.94 (br. s., 1 H), 8.04-8.13 (m,1 H), 7.64-7.77 (m, 1 H), 7.16- 7.51 (m, 4 H), 7.02 (td, J = 2.8, 0.7Hz, 1 H), 6.07- 6.33 (m, 1 H), 3.60-4.11 (m, 6 H), 3.26-3.39 (m, 1 H),3.03-3.17 (m, 1 H), 2.92 (br. s., 3 H), 1.76-2.09 (m, 3 H), 1.13-1.48(m, 8 H). 142

597   ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.76 (br. s., 1 H), 7.86 (d, J =5.4 Hz, 1 H), 7.54-7.62 (m, 1 H), 7.46- 7.54 (m, 2 H), 7.42 (t, J = 7.4Hz, 1 H), 7.33 (t, J = 6.2 Hz, 1 H), 7.24-7.30 (m, 1 H), 6.60 (s, 2 H),5.68 (d, J = 5.3 Hz, 1 H), 3.97 (br. s., 4 H), 3.29 (br. s., 4 H) 143

577   ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.88 (br. s., 1 H), 7.82 (d, J =5.4 Hz, 1 H), 7.61-7.75 (m, 1 H), 7.42 (td, J = 7.0, 2.9 Hz, 1 H),7.16-7.34 (m, 4 H), 6.54 (br. s., 2 H), 5.63 (d, J = 5.3 Hz, 1 H), 3.77(d, J = 12.1 Hz, 2 H), 3.61-3.72 (m, 2 H), 2.73 (t, J = 11.6 Hz, 2 H),1.14 (d, J = 6.1 Hz, 6 H) 144

546   ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.76 (s, 1 H), 7.97 (d, J = 5.1Hz, 1 H), 7.45-7.64 (m, 3 H), 7.32- 7.45 (m, 2 H), 7.20-7.33 (m, 1 H),6.76 (s, 2 H), 5.84 (d, J = 5.1 Hz, 1 H), 2.98 (tt, J = 11.0, 3.4 Hz, 1H), 2.07 (d, J = 10.8 Hz, 2 H), 1.72-1.84 (m, 2 H), 1.67 (d, J = 12.5Hz, 1 H), 1.32-1.56 (m, 5 H) 145

516   ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.51 (1 H, s) 7.96 (1 H, d, J =5.13 Hz) 7.52 (1 H, d, J = 6.41 Hz) 7.44-7.50 (1 H, m) 7.41 (1 H, t, J =7.60 Hz) 7.33 (1 H, t, J = 6.23 Hz) 7.22-7.29 (2 H, m) 6.75 (2 H, s)5.86 (1 H, d, J = 5.13 Hz) 2.29 (3 H, s) 1.40 (9 H, s) 146

498   ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.23 (1 H, s) 7.95 (1 H, d, J =5.31 Hz) 7.61 (2 H, m, J = 8.06 Hz) 7.43 (1 H, td, J = 7.37, 1.92 Hz)7.33 (2 H, m, J = 8.06 Hz) 7.18-7.30 (2 H, m) 6.75 (2 H, s) 5.78 (1 H,d, J = 5.13 Hz) 2.32 (3 H, s) 1.39 (9 H, s) 147

498   ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.26 (1 H, s) 7.96 (1 H, d, J =5.31 Hz) 7.49-7.60 (2 H, m) 7.36- 7.47 (3 H, m) 7.17-7.33 (2 H, m) 6.75(2 H, s) 5.84 (1 H, d, J = 5.13 Hz) 2.32 (3 H, s) 1.40 (9 H, s) 148

580   free base ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.59 (s, 1 H) 8.10 (d,J = 5.2 Hz, 1 H) 7.82-7.99 (m, 1 H) 7.30-7.48 (m, 3 H) 7.26 (t, J = 9.3Hz, 1 H) 6.97 (d, J = 3.5 Hz, 1 H) 6.57 (dd, J = 3.3, 1.60 Hz, 1 H)6.14-6.25 (m, 1 H) 3.17-3.44 (m, 3 H) 3.03-3.17 (m, 2 H) 2.92 (s, 3 H)1.80-1.97 (m, 2 H) 1.32 (d, J = 6.9 Hz, 6 H) 149

606   ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.33 (s, 1 H) 8.03 (d, J = 5.1Hz, 1 H) 7.39-7.56 (m, 3 H) 7.28 (t, J = 7.9 Hz, 1 H) 7.04-7.26 (m, 4 H)6.06 (dd, J = 2.5, 1.45 Hz, 1 H) 3.83 (s, 3 H) 3.54-3.75 (m, 2 H) 3.38(s, 2 H) 3.22-3.31 (m, 1 H) 3.01 (s, 3 H) 1.35 (d, J = 6.8 Hz, 6 H) 150

661   ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.28 (s, 1 H) 7.98 (d, J = 0.8Hz, 1 H) 7.37-7.49 (m, 2 H) 7.23-7.30 (m, 1 H) 7.21 (s, 1 H) 7.08-7.21(m, 3 H) 7.06 (d, J = 7.5 Hz, 1 H) 5.85-6.18 (m, 1 H) 3.79 (s, 3 H) 3.47(d, J = 10.7 Hz, 2 H) 3.24-3.25 (m, 1 H) 3.13-3.25 (m, 1 H) 2.83 (s, 3H) 2.69-2.82 (m, 2 H) 1.78-1.93 (m, 2 H) 1.40-1.57 (m, 2 H) 1.31 (d, J =6.9 Hz, 6 H) 151

621   ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.60 (s, 1 H) 8.12 (d, J = 5.0Hz, 1 H) 7.92 (s, 1 H) 7.14-7.44 (m, 4H) 6.96 (d, J = 3.2 Hz, 1 H) 6.57(dd, J = 3.0, 1.46 Hz, 1 H) 6.07-6.36 (m, 1 H) 3.53-3.88 (m, 1 H) 3.37-3.53 (m, 2 H) 3.17-3.25 (m, 1 H) 2.63-2.86 (m, 5 H) 1.85 (ddd, J = 4.7,2.2, 1.0 Hz, 2 H) 1.42-1.60 (m, 2H) 1.32 (d, J = 6.9 Hz, 6 H) 152

574   ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.04 (s, 1 H) 7.91 (d, J = 5.1Hz, 1 H) 7.37-7.47 (m, 2 H) 7.30-7.38 (m, 1 H) 7.27 (t, J = 6.0 Hz, 1 H)7.05-7.26 (m, 3 H) 5.64-5.86 (m, 1 H) 3.71 (s, 3 H) 3.17-3.26 (m, 1 H)2.78-3.12 (m, 2 H) 1.66-1.85 (m, 1 H) 1.30 (d, J = 6.9 Hz, 6 H)0.75-0.87 (m, 6 H) 153

679   ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.09 (s, 1 H) 8.00 (br. s., 1 H)7.38-7.51 (m, 2 H) 7.35 (t, J = 6.9 Hz, 1 H) 7.10-7.32 (m, 4 H)5.70-6.09 (m, 1 H) 3.67- 3.82 (m, 3 H) 3.48 (dd, J = 1.7, 1.1 Hz, 3 H)3.26 (d, J = 6.8 Hz, 1 H) 2.85 (s, 3 H) 2.64-2.82 (m, 2 H) 1.74-1.95 (m,2 H) 1.39-1.59 (m, 2 H) 1.32 (d, J = 6.8 Hz, 6 H) 154

516   ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.59 (s, 1 H) 8.06 (d, J = 5.1Hz, 1 H) 7.91 (s, 1 H) 7.27-7.40 (m, 3H) 7.24 (t, J = 7.8 Hz, 1 H) 7.04(d, J = 3.2 Hz, 1 H) 6.56 (dd, J = 3.2, 1.7 Hz, 1 H) 5.77-6.01 (m, 1 H)3.22-3.27 (m, 1 H) 2.83-3.12 (m, 2 H) 1.64-1.95 (m, 1 H) 1.33 (d, J =6.9 Hz, 6 H) 0.74-0.91 (m, 6 H) 155

509   ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.56 (s, 1 H) 8.83 (d, J = 2.3Hz, 1 H) 8.74 (dd, J = 4.8, 1.0 Hz, 1 H) 8.04-8.15 (m, 1 H) 7.98 (d, J =5.1 Hz, 1 H) 7.56 (dd, J = 8.1, 4.9 Hz, 1 H) 7.25-7.38 (m, 2 H)7.04-7.25 (m, 3 H) 5.91-6.05 (m, 1 H) 3.17-3.27 (m, 1 H) 2.87- 3.11 (m,2 H) 1.65-1.86 (m, 1 H) 1.22-1.38 (m, 6 H) 0.71-0.89 (m, 6 H) 156

565   (400 MHz, DMSO-d₆) δ ppm 10.76 (br. s., 1 H), 7.91 (d, J = 6.5 Hz,1 H), 7.52-7.60 (m, 3 H), 7.47-7.52 (m, 3 H), 7.39 (dd, J = 5.8, 3.5 Hz,1 H), 5.60 (d, J = 6.5 Hz, 1 H), 3.68-3.77 (m, 4 H), 3.55 (d, J = 4.3Hz, 4 H) 157

520   ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.43 (s, 1 H), 8.05 (d, J = 5.1Hz, 1 H), 7.37-7.67 (m, 5 H), 7.23 (t, J = 8.8 Hz, 1 H), 6.77 (br. s., 2H), 5.82 (d, J = 5.1 Hz, 1 H), 1.37 (s, 9 H). 158

512.1 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.47 (s, 1 H), 7.96 (d, J = 4.8Hz, 1 H), 7.44-7.58 (m, 4 H), 7.28 (t, J = 7.6 Hz, 1 H), 7.15-7.18 (m, 4H), 7.08 (d, J = 7.3 Hz, 1 H), 5.97 (s, 1 H), 3.93 (bs, 1 H), 3.23 (m, 1H), 1.30 (d, J = 6.6 Hz, 6 H), 1.09 (d, J = 7.1 Hz, 6 H) 159

564.2 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.88 (s, 1 H), 8.00 (d, J = 4.4Hz, 1 H), 7.60 (bs, 1 H), 7.35 (d, J = 7.9 Hz, 1 H), 7.06-7.21 (m, 5 H),6.12 (s, 1 H), 3.34- 3.41 (m, 4 H), 3.22-3.26 (m, 1 H), 3.21 (s, 3 H),1.31 (d, J = 6.9 Hz, 6 H) 160

550.2 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.93 (s, 1 H), 8.02 (d, J = 4.9Hz, 1 H), 7.60 (s, 1 H), 7.39 (d, J = 7.9 Hz, 1 H), 7.05-7.25 (m, 5 H),6.14 (s, 1 H), 4.66 (s, 1 H), 3.51 (bs, 2 H), 3.23-3.30 (m, 1 H), 1.36(d, J = 7.0 Hz, 6 H) 161

577.2 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.00 (d, J = 5.3 Hz, 1 H),7.40-7.48 (m, 1 H), 7.35 (d, J = 7.5 Hz, 1 H), 7.22 (t, J = 5.4 Hz, 1H), 6.98-7.07 (m, 3 H), 6.88 (s, 1 H), 6.22 (s, 1 H), 3.24-3.31 (m, 1H), 2.85 (bs, 2 H), 2.53 (s, 6 H), 1.35 (d, J = 6.9 Hz, 6 H) 162

578.2 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.93 (s, 1 H), 8.08 (d, J = 5.1Hz, 1 H), 7.72 (t, J = 4.4 Hz, 1 H), 7.39-7.45 (m, 2 H), 7.24-7.30 (m, 3H), 7.11 (d, J = 8.0 Hz, 1 H), 6.17 (s, 1 H), 3.38-3.41 (m, 1 H),3.27-3.31 (m, 2 H), 3.26 (s, 3 H), 1.36 (d, J = 6.8 Hz, 6H), 1.12 (d, J= 6.6 Hz, 3 H) 163

591.2 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.02 (s, 1 H), 7.40 (t, J = 8.4Hz, 1 H), 7.26-7.32 (m, 2 H), 6.92- 7.05 (m, 4 H), 6.28 (bs, 1 H),3.25-3.30 (m, 1 H), 2.84 (t, J = 7.2 Hz, 2 H), 2.60 (s, 6 H), 1.76 (bs,2 H), 1.36 (d, J = 6.9 Hz, 6 H) 164

603.3 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.01 (d, J = 5.1 Hz, 1 H),7.33-7.41 (m, 2 H), 7.28 (s, 1 H), 6.95- 7.03 (m, 4 H), 6.80 (s, 1 H),6.24 (bs, 1 H), 3.48 (s, 2 H), 3.23-3.30 (m, 1 H), 3.04 (s, 4 H), 1.85(s, 4 H), 1.36 (d, J = 6.8 Hz, 6 H) 165

619.3 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.05 (d, J = 5.1 Hz, 1 H),7.61-7.68 (m, 1 H), 7.42 (d, J = 6.1 Hz, 1 H), 7.17-7.25 (m, 5 H), 7.13(t, J = 5.3 Hz, 1 H), 6.18 (s, 1 H), 3.58 (t, J = 4.3 Hz, 4 H),3.25-3.32 (m, 1 H), 2.52 (s, 2 H), 2.47 (s, 4 H), 1.36 (d, J = 7.0 Hz, 6H) 166

594.2 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.93 (s, 1 H), 8.06 (d, J = 5.1Hz, 1 H), 7.67 (bs, 1 H), 7.41 (d, J = 7.7 Hz, 1 H), 7.17-7.32 (m, 4 H),6.18 (s, 1 H), 4.62 (t, J = 5.3 Hz, 1 H), 3.41-3.54 (m, 8 H), 3.25-3.32(m, 1 H), 1.36 (d, J = 6.6 Hz, 6 H) 167

605.3 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.98 (d, J = 5.2 Hz, 1 H), 7.39(t, J = 7.4 Hz, 1 H), 7.24-7.31 (m, 2 H), 6.93-7.02 (m, 3 H), 6.80 (bs,1 H), 6.22 (bs, 1 H), 3.23-3.30 (m, 1 H), 3.19 (bs, 4 H), 2.84 (t, J =7.6 Hz, 2 H), 2.61 (s, 6 H), 1.56 (bs, 2 H), 1.49 (bs, 2 H), 1.35 (d, J= 7.0 Hz, 6 H) 168

578.2 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.93 (s, 1 H), 8.06 (d, J = 5.1Hz, 1 H), 7.67 (t, J = 6.6 Hz, 1 H), 7.42 (dd, J = 2.1, 7.6 Hz, 1 H),7.20-7.31 (m, 5 H), 6.17 (s, 1 H), 3.25-3.38 (m, 5 H), 3.13 (s, 3 H),1.75 (t, J = 6.6 Hz, 2 H), 1.36 (d, J = 7.0 Hz, 6 H) 169

591.2 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.02 (s, 1 H), 7.40 (t, J = 8.4Hz, 1 H), 7.26-7.32 (m, 2 H), 6.92- 7.05 (m, 4 H), 6.28 (bs, 1 H),3.25-3.30 (m, 1 H), 2.84 (t, J = 7.2 Hz, 2 H), 2.60 (s, 6 H), 1.76 (bs,2 H), 1.36 (d, J = 6.9 Hz, 6 H) 170

603.3 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.01 (d, J = 5.1 Hz, 1 H),7.33-7.41 (m, 2 H), 7.28 (s, 1 H), 6.95- 7.03 (m, 4 H), 6.80 (s, 1 H),6.24 (bs, 1 H), 3.48 (s, 2 H), 3.23-3.30 (m, 1 H), 3.04 (s, 4 H), 1.85(s, 4 H), 1.36 (d, J = 6.8 Hz, 6 H) 171

619.3 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.05 (d, J = 5.1 Hz, 1 H),7.61-7.68 (m, 1 H), 7.42 (d, J = 6.1 Hz, 1 H), 7.17-7.25 (m, 5 H), 7.13(t, J = 5.3 Hz, 1 H), 6.18 (s, 1 H), 3.58 (t, J = 4.3 Hz, 4 H),3.25-3.32 (m, 1 H), 2.52 (s, 2 H), 2.47 (s, 4 H), 1.36 (d, J = 7.0 Hz, 6H) 172

594.2 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.93 (s, 1 H), 8.06 (d, J = 5.1Hz, 1 H), 7.67 (bs, 1 H), 7.41 (d, J = 7.7 Hz, 1 H), 7.17-7.32 (m, 4 H),6.18 (s, 1 H), 4.62 (t, J = 5.3 Hz, 1 H), 3.41-3.54 (m, 8 H), 3.25-3.32(m, 1 H), 1.36 (d, J = 6.6 Hz, 6 H) 173

605.3 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.98 (d, J = 5.2 Hz, 1 H), 7.39(t, J = 7.4 Hz, 1 H), 7.24-7.31 (m, 2 H), 6.93-7.02 (m, 3 H), 6.80 (bs,1 H), 6.22 (bs, 1 H), 3.23-3.30 (m, 1 H), 3.19 (bs, 4 H), 2.84 (t, J =7.6 Hz, 2 H), 2.61 (s, 6 H), 1.56 (bs, 2 H), 1.49 (bs, 2 H), 1.35 (d, J= 7.0 Hz, 6 H) 174

578.2 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.93 (s, 1 H), 8.06 (d, J = 5.1Hz, 1 H), 7.67 (t, J = 6.6 Hz, 1 H), 7.42 (dd, J = 2.1, 7.6 Hz, 1 H),7.20-7.31 (m, 5 H), 6.17 (s, 1 H), 3.25-3.38 (m, 5 H), 3.13 (s, 3 H),1.75 (t, J = 6.6 Hz, 2 H), 1.36 (d, J = 7.0 Hz, 6 H) 175

667.1 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.94 (s, 1 H), 8.06 (d, J = 5.0Hz, 1 H), 7.66 (t, J = 6.9 Hz, 1 H), 7.42 (d, J = 6.8 Hz, 1 H),7.18-7.27 (m, 5 H), 6.19 (s, 1 H), 3.24-3.31 (m, 1 H), 3.07 (s, 4 H),2.96 (s, 4 H), 2.65 (t, J = 6.1 Hz, 2 H), 1.36 (d, J = 6.8 Hz, 6 H) 176

562.2 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.88 (s, 1 H), 8.02 (d, J = 5.3Hz, 1 H), 7.67 (t, J = 8.4 Hz, 1 H), 7.42 (t, J = 7.3 Hz, 1 H),7.21-7.36 (m, 5 H), 5.92 (bs, 1 H), 3.25-3.31 (m, 1 H), 3.05 (bs, 1 H),2.96 (bs, 1 H), 1.81 (bs, 1 H), 1.35 (d, J = 6.9 Hz, 6 H), 0.86 (d, J =6.6 Hz, 6 H) 177

584.0 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.76 (s, 1 H), 8.12 (d, J = 5.1Hz, 1 H), 7.63 (t, J = 6.2 Hz, 1 H), 7.36-7.59 (m, 5 H), 7.28 (t, J =7.9 Hz, 1 H), 6.04 (bs, 2 H), 3.55 (bs, 2H), 1.41 (s, 9 H) 178

552.1 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.93 (s, 1 H), 8.11 (d, J = 5.2Hz, 1 H), 7.72 (t, J = 7.4 Hz, 1 H), 7.48 (t, J = 5.7 Hz, 1 H),7.38-7.44 (m, 2 H), 7.24-7.30 (m, 3 H), 6.23 (bs, 1 H), 4.56 (bs, 1 H),4.45 (bs, 1 H), 3.57 (bs, 1 H), 3.51 (bs, 1 H), 3.26-3.31 (m, 1 H), 1.36(d, J = 6.9 Hz, 6 H) 179

566.2 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.76 (s, 1 H), 8.07 (d, J = 5.1Hz, 1 H), 7.35-7.57 (m, 6 H), 7.28 (t, J = 7.8 Hz, 1 H), 6.01 (bs, 1 H),4.53 (bs, 1 H), 4.41 (bs, 1 H), 3.47 (bs, 2 H), 1.40 (s, 9 H) 180

602.1 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.93 (s, 1 H), 8.13 (d, J = 5.1Hz, 1 H), 7.72 (t, J = 8.5 Hz, 1 H), 7.38- 7.48 (m, 3 H), 7.24-7.30 (m,3 H), 6.26 (bs, 1 H), 3.46 (bs, 2 H), 3.25-3.32 (m, 1 H), 2.51 (bs, 2H), 1.36 (d, J = 6.8 Hz, 6 H) 181

589.1 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.98 (s, 1 H), 8.45 (d, J = 5.2Hz, 1 H), 7.67 (t, J = 6.7 Hz, 6 H), 7.41 (d, J = 7.6 Hz, 1 H), 7.35(bs, 1 H), 7.28 (t, J = 9.4 Hz, 1 H), 7.24 (t, J = 9.0 Hz, 2 H), 6.84(d, J = 5.2 Hz, 1 H), 4.94 (q, J = 8.9 Hz, 2 H), 3.28-3.31 (m, 1 H),1.38 (d, J = 7.1 Hz, 9 H) 182

605.3 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.76 (s, 1 H), 7.86 (d, J = 3.2Hz, 1 H), 7.46-7.59 (m, 3 H), 7.41 (t, J = 7.4 Hz, 1 H), 7.23-7.31 (m, 2H), 7.15 (bs, 1 H), 5.62 (s, 1 H), 3.71 (s, 4 H), 3.45 (s, 4 H), 3.01(bs, 2 H), 1.79-1.85 (m, 1 H), 0.87 (d, J = 6.4 Hz, 6 H) 183

591   ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.93 (s, 1 H), 8.08 (d, J = 5.1Hz, 1 H), 7.87-8.00 (m, 1 H), 7.64- 7.79 (m, 1 H), 7.34-7.50 (m, 2 H),7.21-7.33 (m, 4 H), 6.12-6.28 (m, 1 H), 3.25-3.32 (m, 3 H), 3.17- 3.24(m, 2 H), 1.80 (s, 3 H), 1.36 (d, J = 6.9 Hz, 6 H) 184

631   ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.80 (s, 1 H), 8.10 (d, J = 4.7Hz, 1 H), 7.46-7.68 (m, 3 H), 7.39 (d, J = 6.5 Hz, 2 H), 7.20-7.33 (m, 2H), 6.19 (br. s., 1 H), 3.16-3.25 (m, 4 H), 2.21 (t, 2 H), 1.85-1.97 (m,2 H), 1.63-1.74 (m, 2 H), 1.36 (d, J = 6.8 Hz, 6 H) 185

631   ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.76 (s, 1 H), 8.03 (d, J = 5.1Hz, 1 H), 7.45-7.61 (m, 3 H), 7.32- 7.45 (m, 2 H), 7.18-7.32 (m, 2 H),5.87 (br. s., 1 H), 3.08-3.25 (m, 4 H), 2.22 (t, J = 8.0 Hz, 2 H), 1.85-1.98 (m, 2 H), 1.66 (br. s., 2 H), 1.35 (d, J = 6.9 Hz, 6 H) 186

591   ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.80 (s, 1 H), 8.10 (d, J = 4.7Hz, 1 H), 7.92 (br. s., 1 H), 7.45-7.67 (m, 3 H), 7.39 (d, J = 6.7 Hz, 2H), 7.23-7.33 (m, 2 H), 6.20 (br. s., 1 H), 3.25-3.32 (m, 2 H),3.13-3.25 (m, 2 H), 1.80 (s, 3 H), 1.36 (d, J = 6.9 Hz, 6 H) 187

591   ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.76 (s, 1 H), 8.04 (d, J = 5.2Hz, 1 H), 7.91 (br. s., 1 H), 7.45-7.63 (m, 3 H), 7.32-7.45 (m, 2 H),7.22-7.31 (m, 2 H), 5.90 (br. s., 1 H), 3.14-3.31 (m, 5 H), 1.80 (s, 3H), 1.35 (d, J = 6.9 Hz, 6 H) 188

674   ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.76 (s, 1 H), 7.87 (d, J = 5.1Hz, 1 H), 7.45-7.63 (m, 3 H), 7.37- 7.45 (m, 1 H), 7.22-7.33 (m, 2 H),7.06 (br. s., 1 H), 5.60-5.68 (m, 1 H), 3.66-3.75 (m, 4 H), 3.41-3.52(m, 4 H), 3.11-3.26 (m, 4 H), 2.21 (t, J = 8.1 Hz, 2 H), 1.84-1.98 (m, 2H), 1.59-1.74 (m, 2 H) 189

649   ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.75 (s, 1 H), 8.03 (d, J = 5.1Hz, 1 H), 7.13-7.66 (m, 7 H), 6.84 (br. s., 1 H), 5.80-6.02 (m, 1 H),3.19-3.31 (m, 3 H), 3.02-3.13 (m, 2 H), 1.30-1.41 (m, 15 H) 190

617   ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.77 (s, 1 H), 8.04 (d, J = 4.6Hz, 1 H), 7.14-7.69 (m, 7 H), 5.90 (br. s., 1 H), 3.39 (t, J = 6.7 Hz, 2H), 2.17 (t, J = 7.8 Hz, 2 H), 1.81-1.94 (m, 2 H), 1.35 (d, J = 6.8 Hz,6 H) 191

627   ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.76 (s, 1 H), 8.05 (d, J = 5.1Hz, 1 H), 7.19-7.64 (m, 7 H), 7.10 (t, J = 5.5 Hz, 1 H), 5.91 (br. S., 1H), 3.24-3.31 (m, 2 H), 3.04-3.16 (m, 2 H), 2.90 (s, 3 H), 1.35 (d, J =7.0 Hz, 6 H) 192

607   ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.76 (br. s., 1 H), 8.04 (d, J =5.1 Hz, 1 H), 7.77-7.98 (m, 1 H), 7.18- 7.62 (m, 7 H), 5.82-6.02 (m, 1H), 5.49 (t, J = 5.5 Hz, 1 H), 3.80 (d, J = 5.3 Hz, 2 H), 3.18-3.32 (m,4 H), 1.35 (d, J = 7.0 Hz, 6 H) 193

663   ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.75 (s, 1 H), 8.02 (d, J = 4.9Hz, 1 H), 7.14-7.66 (m, 8 H), 6.79 (br. s., 1 H), 5.79-5.97 (m, 1 H),3.10-3.31 (m, 3 H), 2.91-3.01 (m, 2 H), 1.59 (br. s., 2 H), 1.32-1.40(m, 15 H) 194

605   ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.76 (s, 1 H), 8.03 (d, J = 4.9Hz, 1 H), 7.83 (br. s., 1 H), 7.16-7.64 (m, 7 H), 5.87 (br. s., 1 H),3.13-3.30 (m, 3 H), 3.02- 3.10 (m, 2 H), 1.80 (s, 3 H), 1.60 (br. s., 2H), 1.35 (d, J = 6.8 Hz, 6 H) 195

641   ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.76 (s, 1 H), 8.03 (d, J = 5.1Hz, 1 H), 7.21-7.61 (m, 7 H), 6.97 (d, J = 4.9 Hz, 1 H), 5.89 (br. s., 1H), 3.16-3.30 (m, 3 H), 2.94-3.02 (m, 2 H), 2.88 (s, 3 H), 1.70 (br. s.,2 H), 1.35 (d, J = 6.8 Hz, 6 H) 196

621   ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.76 (s, 1 H), 8.02 (d, J = 5.1Hz, 1 H), 7.73-7.91 (m, 1 H), 7.20- 7.64 (m, 8 H), 5.80-5.96 (m, 1 H),3.79 (s, 2 H), 3.22- 3.31 (m, 3 H), 3.07-3.20 (m, 3 H), 1.63 (br. s., 2H), 1.35 (d, J = 6.8 Hz, 6 H) 197

605   ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.71 (br. s., 1 H), 8.04 (d, J =5.1 Hz, 1 H), 7.91 (d, J = 1.5 Hz, 1 H), 7.12-7.67 (m, 7 H), 5.83-6.09(m, 1 H), 3.08-3.28 (m, 4 H), 1.80 (s, 3 H), 1.41 (s, 9 H) 198

663   ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.75 (s, 1 H), 8.03 (d, J = 5.1Hz, 1 H), 7.13-7.67 (m, 7 H), 6.85 (br. s., 1 H), 5.80-6.02 (m, 1 H),3.16-3.28 (m, 2 H), 2.99-3.13 (m, 2 H), 1.40 (s, 9 H), 1.37 (s, 9 H) 199

641   ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.75 (s, 1 H), 8.05 (d, J = 5.1Hz, 1 H), 7.23-7.64 (m, 7 H), 7.10 (t, J = 5.7 Hz, 1 H), 5.91 (br. s., 1H), 3.05-3.15 (m, 2 H), 2.91 (s, 3H), 1.40 (s, 9 H) 200

531   ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.85 (s, 1 H), 7.74 (d, J = 5.3Hz, 1 H), 7.40-7.63 (m, 3 H), 7.29 (t, J = 8.2 Hz, 1 H), 7.04-7.19 (m, 3H), 6.52 (s, 2 H), 5.75 (d, J = 5.3 Hz, 1 H), 3.67 (t, J = 4.6 Hz, 4 H),3.40 (t, J = 4.6 Hz, 4 H) 201

612   ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.81 (br. s., 1 H), 8.15 (d, J =5.0 Hz, 1 H), 7.45-7.67 (m, 4 H), 7.36-7.45 (m, 2 H), 7.29 (dd, J =10.0, 8.6 Hz, 1 H), 6.22-6.32 (m, 1 H), 3.59-3.77 (m, 2 H), 3.34-3.40(m, 2 H), 3.30 (s, 1 H), 3.02 (s, 3 H), 1.36 (d, J = 6.9 Hz, 6 H) 202

655   ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.93 (s, 1 H), 7.96 (d, J = 5.2Hz, 1 H), 7.66-7.78 (m, 1 H), 7.38 (d, J = 6.4 Hz, 2 H), 7.28 (q, J =9.0 Hz, 4 H), 6.06 (d, J = 5.0 Hz, 1 H), 3.72 (t, J = 4.6 Hz, 4 H), 3.66(q, J = 6.6 Hz, 2 H), 3.46 (t, J = 4.6 Hz, 4 H), 3.02 (s, 3 H) 203

626   ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.87 (s, 1 H), 8.09 (d, J = 5.2Hz, 1 H), 7.61-7.75 (m, 1 H), 7.40- 7.47 (m, 2 H), 7.37 (t, J = 6.2 Hz,1 H), 7.30 (d, J = 7.9 Hz, 1 H), 7.24 (t, J = 9.1 Hz, 2 H), 5.98 (br.s., 1 H), 3.54-3.74 (m, 2 H), 3.34-3.39 (m, 2 H), 2.47-2.55 (m, 3 H),1.41 (s, 9 H) 204

626   ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.81 (s, 1 H), 8.11 (d, J = 5.1Hz, 1 H), 7.35-7.67 (m, 6 H), 7.29 (t, J = 9.3 Hz, 1 H), 6.21 (br. s., 1H), 3.36-3.46 (m, 1 H), 3.24-3.32 (m, 2 H), 3.10-3.21 (m, 2 H), 2.97 (s,3 H), 1.87-2.02 (m, 2 H), 1.36 (d, J = 6.9 Hz, 6 H) 205

638   ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.83 (s, 1 H), 8.16 (d, J = 5.1Hz, 1 H), 7.46-7.70 (m, 4 H), 7.35- 7.47 (m, 2 H), 7.30 (dd, J = 10.0,8.6 Hz, 1 H), 6.28 (br. s., 1 H), 3.25-3.33 (m, 1 H), 3.05-3.27 (m, 4H), 1.93-2.25 (m, 5 H), 1.38 (d, J = 6.8 Hz, 6 H) 206

587   ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.85 (s, 1 H), 7.76 (d, J = 5.3Hz, 1 H), 7.39-7.61 (m, 3 H), 7.29 (t, J = 8.2 Hz, 1 H), 7.02-7.22 (m, 4H), 5.74 (d, J = 4.1 Hz, 1 H), 3.67 (t, J = 4.6 Hz, 4 H), 3.40 (t, J =4.5 Hz, 4 H), 2.99 (t, J = 6.3 Hz, 2 H), 1.79 (dt, J = 13.4, 6.7 Hz, 1H), 0.83 (d, J = 6.7 Hz, 6 H) 207

621   ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.70 (s, 1 H), 7.82 (d, J = 5.2Hz, 1 H), 7.40-7.57 (m, 3 H), 7.32- 7.40 (m, 1 H), 7.16-7.29 (m, 2 H),7.03 (br. s., 1 H), 5.60 (d, J = 4.3 Hz, 1 H), 3.66 (t, J = 4.6 Hz, 4H), 3.40 (t, J = 4.4 Hz, 4 H), 3.24-3.36 (m, 4 H), 3.18 (s, 3 H), 1.68(quin, J = 6.6 Hz, 2 H) 208

593   ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.70 (s, 1 H), 7.82 (d, J = 5.3Hz, 1 H), 7.40-7.58 (m, 2 H), 7.37 (td, J = 7.3, 1.9 Hz, 1 H), 7.16-7.30(m, 2 H), 6.89 (br. s., 1 H), 5.59 (d, J = 5.1 Hz, 1 H), 4.60 (t, J =4.7 Hz, 1 H), 4.05 (q, J = 5.0 Hz, 1 H), 3.66 (t, J = 4.6 Hz, 4 H),3.36- 3.51 (m, 5 H), 3.23 (d, J = 5.7 Hz, 1 H), 3.12 (d, J = 4.8 Hz, 2H) 209

631 [M − H]⁻ ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.70 (s, 1 H), 7.82 (d, J= 5.22 Hz, 1 H), 7.40-7.59 (m, 3 H), 7.31- 7.41 (m, 1 H), 7.15-7.30 (m,2 H), 6.99 (br. s., 1 H), 5.61 (d, J = 4.67 Hz, 1 H), 3.86-3.97 (m, 1H), 3.61- 3.78 (m, 5 H), 3.56 (q, J = 7.20 Hz, 1 H), 3.41 (t, J = 4.39Hz, 4 H), 3.06-3.21 (m, 2 H), 1.63-1.92 (m, 3 H), 1.39-1.61 (m, 1 H) 210

564   ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.74 (s, 1 H), 8.03 (d, J = 5.1Hz, 1 H), 7.52-7.63 (m, 1 H), 7.50 (dd, J = 9.0, 4.1 Hz, 2 H), 7.41 (t,J = 7.5 Hz, 1 H), 7.36 (t, J = 6.4 Hz, 1 H), 7.28 (t, J = 7.8 Hz, 1 H),7.12 (t, J = 5.6 Hz, 1 H), 5.89 (d, J = 1.7 Hz, 1 H), 4.65 (br. s., 1H), 3.49 (d, J = 4.3 Hz, 2 H), 3.33 (s, 2 H), 1.40 (s, 9 H) 211

593   ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.70 (s, 1 H), 7.98 (d, J = 5.1Hz, 1 H), 7.40-7.57 (m, 3 H), 7.36 (t, J = 7.4 Hz, 1 H), 7.31 (t, J =6.5 Hz, 1 H), 7.14-7.27 (m, 2 H), 5.58-6.16 (m, 1 H), 3.25-3.40 (m, 4H), 3.18 (s, 3 H), 1.67 (br. s., 2 H), 1.36 (s, 9 H) 212

592   ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.75 (s, 1 H), 8.04 (d, J = 5.1Hz, 1 H), 7.53-7.63 (m, 1 H), 7.44- 7.53 (m, 2 H), 7.41 (t, J = 7.5 Hz,1 H), 7.36 (t, J = 6.3 Hz, 1 H), 7.28 (t, J = 7.8 Hz, 1 H), 7.21 (t, J =5.6 Hz, 1 H), 5.75-6.06 (m, 1 H), 3.44 (q, J = 7.0 Hz, 4 H), 3.27-3.40(m, 2 H), 1.40 (s, 9 H), 1.10 (t, J = 7.0 Hz, 3 H) 213

604   ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.75 (s, 1 H), 8.03 (d, J = 5.13Hz, 1 H), 7.45-7.62 (m, 2 H), 7.41 (t, J = 7.37 Hz, 1 H), 7.36 (t, J =6.41 Hz, 1 H), 7.28 (d, J = 7.78 Hz, 1 H), 7.15-7.26 (m, 1 H), 5.64-6.16(m, 1 H), 3.94 (br. s., 1 H), 3.69-3.82 (m, 1 H), 3.61 (q, J = 7.26 Hz,1 H), 3.33 (s, 2 H), 3.02-3.30 (m, 1 H), 1.91 (s, 1 H), 1.71-1.90 (m, 2H), 1.46-1.64 (m, 1 H), 1.40 (s, 9 H) 214

611   ¹H NMR (400 MHz, DMSO-d₆) d ppm 10.70 (s, 1 H) 8.51 (d, J = 5.3Hz, 1 H) 7.47-7.56 (m, 1 H) 7.33- 7.47 (m, 4 H) 7.27 (t, J = 7.8 Hz, 1H) 6.72 (d, J = 5.5 Hz, 1 H) 3.42-3.52 (m, 2 H) 3.20-3.26 (m, 2 H) 2.99(s, 3 H) 1.38 (s, 9 H) 215

618   ¹H NMR (400 MHz, DMSO-d₆) d ppm 8.47 (d, J = 5.3 Hz, 1 H)7.26-7.54 (m, 6 H) 7.22 (t, J = 7.9 Hz, 1 H) 6.69 (d, J = 5.3 Hz, 1 H)3.52 (t, J = 4.2 Hz, 4 H) 3.27 (br. s., 4 H) 2.96 (t, J = 7.5 Hz, 2 H)2.72 (br. s., 2 H) 1.38 (s, 9 H) 216

666   ¹H NMR (400 MHz, DMSO-d6) d ppm 10.75 (br. s., 1 H), 8.52 (d, J =5.5 Hz, 1 H), 7.45-7.53 (m, 2 H), 7.53- 7.62 (m, 1 H), 7.42 (t, J = 7.7Hz, 2 H), 6.73 (d, 1 H), 7.31 (m, 1 H), 2.98 (m, 2 H), 3.05 (m, 4 H),2.85- 2.95 (m, 6 H), 1.42 (s, 6 H) 217

567   1H NMR (400 MHz, DMSO-d₆) d ppm 10.75 (s, 1 H), 8.56 (d, J = 5.31Hz, 1 H), 7.46 (m, 4 H), 7.54 (m, 1 H), 7.31 (t, J = 7.78 Hz, 1 H), 6.76(d, J = 5.31 Hz, 1 H), 4.00 (t, J = 6.50 Hz, 2 H), 3.29 (m, 2 H), 1.43(s, 9 H).

Example 218N-{3-[5-(2-amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-3-fluorobenzenesulfonamide

Following a procedure analogous to the procedure described inIntermediate 14 using4-[4-(3-amino-2-fluorophenyl)-2-(1,1-dimethylethyl)-1,3-thiazol-5-yl]-2-pyrimidinamine(65 mg, 0.189 mmol) and 3-fluorobenzenesulfonyl chloride (0.030 mL,0.227 mmol), the title compound was obtained as an off white solid (64mg, 67% yield). MS (ESI): 502.2 [M+H]⁺.

Example 219N-{3-[5-(2-amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}benzenesulfonamide

Following a procedure analogous to the procedure described inIntermediate 14 using 44-[4-(3-amino-2-fluorophenyl)-2-(1,1-dimethylethyl)-1,3-thiazol-5-yl]-2-pyrimidinamine(65 mg, 0.189 mmol) and benzenesulfonyl chloride (0.029 mL, 0.227 mmol),the title compound was obtained as an off white solid (60 mg, 65%yield). MS (ESI): 484 [M+H]⁺.

Example 220N-{3-[2-(1,1-dimethylethyl)-5-(2-methyl-4-pyrimidinyl)-1,3-thiazol-4-yl]-2,4-difluorophenyl}-3-fluorobenzenesulfonamide

Step A:N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2,4-difluorophenyl}-3-fluorobenzenesulfonamide

Following a procedure analogous to the procedure described inIntermediate 14 using{3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2,4-difluorophenyl}amine(500 mg, 1.313 mmol) and 3-fluorobenzenesulfonyl chloride (0.210 mL,1.575 mmol), the title compound was obtained as an yellow foam (690 mg,98% yield).

Step B:N-{3-[2-(1,1-dimethylethyl)-5-(2-methyl-4-pyrimidinyl)-1,3-thiazol-4-yl]-2,4-difluorophenyl}-3-fluorobenzenesulfonamide

Following a procedure analogous to the procedure described in Example 25usingN-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2,4-difluorophenyl}-3-fluorobenzenesulfonamide(100 mg, 0.186 mmol) and dimethylzinc (0.186 mL, 0.371 mmol), the titlecompound was obtained as an off white solid (90 mg, 94% yield). MS(ESI): 519.1 [M+H]⁺.

Example 221N-{3-[2-(1,1-dimethylethyl)-5-(4-pyrimidinyl)-1,3-thiazol-4-yl]-2,4-difluorophenyl}-3-fluorobenzenesulfonamide

Following a procedure analogous to the procedure described in Example 26usingN-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2,4-difluorophenyl}-3-fluorobenzenesulfonamide(150 mg, 0.278 mmol), the title compound was obtained as a yellow solid(85 mg, 60% yield). MS (ESI): 505.1 [M+H]⁺.

Example 222N-{3-[2-(1,1-dimethylethyl)-5-(2-methyl-4-pyrimidinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-3-fluorobenzenesulfonamide

Step A:3-[2-(1,1-dimethylethyl)-5-(4-pyrimidinyl)-1,3-thiazol-4-yl]-2-fluoroaniline

Step A:3-[2-(1,1-dimethylethyl)-5-(2-methyl-4-pyrimidinyl)-1,3-thiazol-4-yl]-2-fluoroaniline

Following a procedure analogous to the procedure described in Example 25using3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluoroaniline(1.0 g, 2.76 mmol) and dimethylzinc (2.76 mL, 5.51 mmol), the titlecompound was obtained as an off white solid (0.8 g, 85% yield). MS(ESI): 343 [M+H]⁺.

Step B:N-{3-[2-(1,1-dimethylethyl)-5-(2-methyl-4-pyrimidinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-3-fluorobenzenesulfonamide

3-[2-(1,1-dimethylethyl)-5-(2-methyl-4-pyrimidinyl)-1,3-thiazol-4-yl]-2-fluoroaniline(70 mg, 0.204 mmol), 3-fluorobenzenesulfonyl chloride (40 mg, 0.204mmol), and pyridine (0.162 mg, 2.04 mmol) were dissolved indichloromethane (2 mL). After 2 h stirring, the reaction mixture wasplaced on silica gel and chromatography (0 to 30% EtOAc/Hexanes over 25min.) to obtainN-{3-[2-(1,1-dimethylethyl)-5-(2-methyl-4-pyrimidinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-3-fluorobenzenesulfonamide(83 mg, 81%). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.41 (s, 1H), 8.42 (d,J=5.49 Hz, 1H), 7.58-7.52 (m, 2H), 7.50-7.42 (m, 2H), 7.39-7.31 (m, 2H),7.24 (t, J=7.87 Hz, 1H), 6.57 (d, J=5.31 Hz, 1H), 2.52 (s, 3H), 1.37 (s,9H); MS (ESI); 499 (M−H)⁻.

Example 223N-{3-[2-(1,1-dimethylethyl)-5-(4-pyrimidinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-3-fluorobenzenesulfonamide

Step A:3-[2-(1,1-dimethylethyl)-5-(4-pyrimidinyl)-1,3-thiazol-4-yl]-2-fluoroaniline

Following a procedure analogous to the procedure described in Example 26using3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluoroaniline(964 mg, 2.66 mmol), the title compound was obtained as a solid (764 mg,88% yield). MS (ESI): 329 [M+H]⁺.

Step B:N-{3-[2-(1,1-dimethylethyl)-5-(4-pyrimidinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-3-fluorobenzenesulfonamide

Following a procedure analogous to the procedure described inIntermediate 14 using3-[2-(1,1-dimethylethyl)-5-(4-pyrimidinyl)-1,3-thiazol-4-yl]-2-fluoroaniline(70 mg, 0.213 mmol) and 3-fluorobenzenesulfonyl chloride (124 mg, 0.639mmol), the title compound was obtained as a solid (76 mg, 73% yield). MS(ESI): 488 [M+H]⁺.

Example 224N-{3-[2-(1,1-dimethylethyl)-5-(4-pyrimidinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2-fluorobenzenesulfonamide

Following a procedure analogous to the procedure described in Example223, Step A using3-[2-(1,1-dimethylethyl)-5-(4-pyrimidinyl)-1,3-thiazol-4-yl]-2-fluoroaniline(70 mg, 0.213 mmol) and 2-fluorobenzenesulfonyl chloride (0.124 mg,0.639 mmol), the title compound was obtained as an off white solid (60mg, 57% yield). MS (ESI): 488 [M+H]⁺.

Example 225N-{3-[2-(1,1-dimethylethyl)-5-(2-methyl-4-pyrimidinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2-fluorobenzenesulfonamide

Following a procedure analogous to the procedure described in Example222, Step A using3-[2-(1,1-dimethylethyl)-5-(2-methyl-4-pyrimidinyl)-1,3-thiazol-4-yl]-2-fluoroaniline(70 mg, 0.204 mmol) and 2-fluorobenzenesulfonyl chloride (0.119 mL,0.613 mmol), the title compound was obtained as a solid (77 mg, 75%yield). ¹H NMR (400 MHz, DMSO-d₆) ppm 10.53 (s, 1H), 8.42 (d, J=5.31 Hz,1H), 7.64-7.69 (m, 1H), 7.59-7.64 (m, 1H), 7.31-7.39 (m, 3H), 7.25 (dt,J=15.29, 7.74 Hz, 2H), 6.51 (d, J=5.31 Hz, 1H), 2.53 (s, 3H), 1.37 (s,9H). MS (ESI): 502.2 [M+H]⁺.

Example 226 ethyl3-{4-[4-(3-{[(2,6-difluorophenyl)sulfonyl]amino}-2-fluorophenyl)-2-(1,1-dimethylethyl)-1,3-thiazol-5-yl]-2-pyrimidinyl}propanoate

To solidN-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide(1 g, 1.85 mmol) was added 3-ethoxy-3-oxopropylzinc bromide 0.5Msolution in THF (31.5 ml, 15.77 mmol) at RT.Bis(tri-t-butylphosphine)palladium (0) (0.095 g, 0.186 mmol) was addedto reaction mixture. The reaction was stirred at RT for several hours.The reaction was check by LCMS. The reaction mixture was quenched intosat'd NH₄Cl and stirred for several hours. A white/grey ppt wasfiltered. The EtOAc was added to filtrate. The EtOAc was separedcontained form the water layer. The water layer was rewashed with EtOAcand the organic extracts combined, dried over MgSO₄, filtered, andconcentrated to dryness to give an orange oil. The crude product wasadded to a silica gel column and eluted with EtOAc with DCM (20% to 60%)and collected fractions to obtain ethyl3-{4-[4-(3-{[(2,6-difluorophenyl)sulfonyl]amino}-2-fluorophenyl)-2-(1,1-dimethylethyl)-1,3-thiazol-5-yl]-2-pyrimidinyl}propanoate(1.12 g, 64%). MS (ESI): 605 [M+H]⁺.

Example 2272,5-difluoro-N-{2-fluoro-3-[2-(4-morpholinyl)-5-(4-pyrimidinyl)-1,3-thiazol-4-yl]phenyl}benzenesulfonamide

Following a procedure analogous to the procedure described in Example 26usingN-{3-[5-(2-chloro-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide(109 mg, 0.192 mmol), the title compound was obtained as a yellow solid(83 mg, 81% yield). MS (ESI): 534.1 [M+H]⁺.

Example 228N-{2-chloro-3-[2-(1,1-dimethylethyl)-5-(4-pyrimidinyl)-1,3-thiazol-4-yl]phenyl}-2,5-difluorobenzenesulfonamide

Following a procedure analogous to the procedure described in Example 26usingN-{2-chloro-3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]phenyl}-2,5-difluorobenzenesulfonamide(100 mg, 0.180 mmol), the title compound was obtained as a yellow solid(45 mg, 48% yield). MS (ESI): 521 [M+H]⁺.

Example 229N-{2-chloro-3-[2-(1,1-dimethylethyl)-5-(2-methyl-4-pyrimidinyl)-1,3-thiazol-4-yl]phenyl}-2,5-difluorobenzenesulfonamide

Following a procedure analogous to the procedure described in Example 25usingN-{2-chloro-3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]phenyl}-2,5-difluorobenzenesulfonamide(200 mg, 0.360 mmol) and dimethyl zinc in toluene (0.360 mL, 0.720mmol), the title compound was obtained as a yellow solid (161 mg, 84%yield). MS (ESI): 535.0 [M+H]⁺.

Example 230N-{3-[5-(2-amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-3-pyridinesulfonamide

Following a procedure analogous to the procedure described inIntermediate 14 using4-[4-(3-amino-2-fluorophenyl)-2-(1,1-dimethylethyl)-1,3-thiazol-5-yl]-2-pyrimidinamine(100 mg, 0.291 mmol) and 3-pyridinesulfonyl chloride (94 mL, 0.430mmol), the title compound was obtained as a tan solid (34 mg, 24%yield). MS (ESI): 485.0 [M+H]⁺.

Example 231N-{3-[5-(2-amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2-furansulfonamide

Following a procedure analogous to the procedure described inIntermediate 14 using4-[4-(3-amino-2-fluorophenyl)-2-(1,1-dimethylethyl)-1,3-thiazol-5-yl]-2-pyrimidinamine(100 mg, 0.291 mmol) and furan-2-sulfonyl chloride (72 mg, 0.437 mmol),the title compound was obtained as a white solid (87 mg, 63% yield). MS(ESI): 474 [M+H]⁺.

Example 232N-{3-[5-(2-amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2-thiophenesulfonamide

Following a procedure analogous to the procedure described inIntermediate 14 using4-[4-(3-amino-2-fluorophenyl)-2-(1,1-dimethylethyl)-1,3-thiazol-5-yl]-2-pyrimidinamine(100 mg, 0.291 mmol) and thiophene-2-sulfonyl chloride (80 mg, 0.437mmol), the title compound was obtained as a white solid (93 mg, 65%yield). MS (ESI): 489.9 [M+H]⁺.

Example 233N-{3-[5-(2-amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-3-thiophenesulfonamide

Following a procedure analogous to the procedure described inIntermediate 14 using4-[4-(3-amino-2-fluorophenyl)-2-(1,1-dimethylethyl)-1,3-thiazol-5-yl]-2-pyrimidinamine(80 mg, 0.233 mmol) and 3-thiophenesulfonyl chloride (47 mg, 0.256mmol), the title compound was obtained as a white solid (68 mg, 56%yield). MS (ESI): 490.0 [M+H]⁺.

Example 234N-{3-[5-(2-amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-3-furansulfonamide

Following a procedure analogous to the procedure described inIntermediate 14 using4-[4-(3-amino-2-fluorophenyl)-2-(1,1-dimethylethyl)-1,3-thiazol-5-yl]-2-pyrimidinamine(80 mg, 0.233 mmol) and 3-furansulfonyl chloride (43 mg, 0.256 mmol),the title compound was obtained as a white solid (71 mg, 61% yield). MS(ESI): 474.0 [M+H]⁺.

Example 235N-{3-[5-(2-amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-4-methyl-2-thiophenesulfonamide

Following a procedure analogous to the procedure described inIntermediate 14 using4-[4-(3-amino-2-fluorophenyl)-2-(1,1-dimethylethyl)-1,3-thiazol-5-yl]-2-pyrimidinamine(80 mg, 0.233 mmol) and 4-methyl-2-thiophenesulfonyl chloride (50 mg,0.256 mmol), the title compound was obtained as a white solid (59 mg,47% yield). MS (ESI): 504 [M+H]⁺.

Example 236N-{3-[5-(2-amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-chlorophenyl}-2,6-difluorobenzenesulfonamide

Following a procedure analogous to the procedure described in Example52, Step B usingN-{2-chloro-3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]phenyl}-2,6-difluorobenzenesulfonamide(156 mg, 0.281 mmol) and ammona in isopropanol (15 mL, 30 mmol), thetitle compound was obtained as a white solid (56 mg, 35% yield). MS(ESI): 536 [M+H]⁺.

Example 237N-{2-chloro-3-[2-(1,1-dimethylethyl)-5-(4-pyrimidinyl)-1,3-thiazol-4-yl]phenyl}-2,6-difluorobenzenesulfonamide

Following a procedure analogous to the procedure described in Example 26usingN-{2-chloro-3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]phenyl}-2,6-difluorobenzenesulfonamide(152 mg, 0.274 mmol), the title compound was obtained as a yellow solid(37 mg, 25% yield). MS (ESI): 521 [M+H]⁺.

Example 238N-{3-[5-(2-amino-4-pyrimidinyl)-2-(tetrahydro-2H-pyran-4-yl)-1,3-thiazol-4-yl]-2-chlorophenyl}-2,6-difluorobenzenesulfonamide

Following a procedure analogous to the procedure described in Example52, Step B usingN-{2-chloro-3-[5-(2-chloro-4-pyrimidinyl)-2-(tetrahydro-2H-pyran-4-yl)-1,3-thiazol-4-yl]phenyl}-2,6-difluorobenzenesulfonamide(156 mg, 0.267 mmol) and ammona in methanol (10 mL, 70 mmol), the titlecompound was obtained as a yellow solid (53 mg, 33% yield). MS (ESI):564 [M+H]⁺.

Example 239N-{2-chloro-3-[2-(1,1-dimethylethyl)-5-(2-methyl-4-pyrimidinyl)-1,3-thiazol-4-yl]phenyl}-2,6-difluorobenzenesulfonamide

Following a procedure analogous to the procedure described in Example 25usingN-{2-chloro-3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]phenyl}-2,6-difluorobenzenesulfonamide(150 mg, 0.270 mmol) and 2N dimethylzinc in toluene (0.27 mL, 0.540mmol), the title compound was obtained as a solid (75 mg, 47% yield). MS(ESI): 535 [M+H]⁺.

Example 240N-{2-chloro-3-[2-(4-morpholinyl)-5-(4-pyrimidinyl)-1,3-thiazol-4-yl]phenyl}-2,5-difluorobenzenesulfonamide

Following a procedure analogous to the procedure described in Example 26usingN-{2-chloro-3-[5-(2-chloro-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]phenyl}-2,5-difluorobenzenesulfonamide(150 mg, 0.257 mmol), the title compound was obtained as a yellow solid(65 mg, 43% yield). MS (ESI): 550 [M+H]⁺.

Example 241N-{3-[5-(2-amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-chlorophenyl}-2,5-difluorobenzenesulfonamide

Following a procedure analogous to the procedure described in Example52, Step B usingN-{2-chloro-3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]phenyl}-2,5-difluorobenzenesulfonamide(100 mg, 0.180 mmol) and ammonium hydroxide (3 mL, 77 mmol), the titlecompound was obtained as an off white solid (88 mg, 87% yield). MS(ESI): 536 [M+H]⁺.

Example 242N-{3-[5-(2-amino-4-pyrimidinyl)-2-(tetrahydro-2H-pyran-4-yl)-1,3-thiazol-4-yl]-2-chlorophenyl}-2,5-difluorobenzenesulfonamide

Following a procedure analogous to the procedure described in Example52, Step B usingN-{2-chloro-3-[5-(2-chloro-4-pyrimidinyl)-2-(tetrahydro-2H-pyran-4-yl)-1,3-thiazol-4-yl]phenyl}-2,5-difluorobenzenesulfonamide(150 mg, 0.257 mmol) and ammonium hydroxide (3 mL, 77 mmol), the titlecompound was obtained as a tan solid (47 mg, 31% yield). MS (ESI): 565[M+H]⁺.

Example 243N-{2-chloro-3-[5-(4-pyrimidinyl)-2-(tetrahydro-2H-pyran-4-yl)-1,3-thiazol-4-yl]phenyl}-2,5-difluorobenzenesulfonamide

Following a procedure analogous to the procedure described in Example 26usingN-{2-chloro-3-[5-(2-chloro-4-pyrimidinyl)-2-(tetrahydro-2H-pyran-4-yl)-1,3-thiazol-4-yl]phenyl}-2,5-difluorobenzenesulfonamide(150 mg, 0.257 mmol), the title compound was obtained as a yellow solid(62 mg, 42% yield). MS (ESI): 549 [M+H]⁺.

Example 2442,5-difluoro-N-{2-fluoro-3-[5-(4-pyrimidinyl)-2-(tetrahydro-2H-pyran-4-yl)-1,3-thiazol-4-yl]phenyl}benzenesulfonamide

Following a procedure analogous to the procedure described in Example 26usingN-{3-[5-(2-chloro-4-pyrimidinyl)-2-(tetrahydro-2H-pyran-4-yl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide(150 mg, 0.265 mmol) and ammonium formate (89 mg, 2.65 mmol), the titlecompound was obtained as a light yellow solid (89 mg, 63% yield). MS(ESI): 533.1 [M+H]⁺.

Example 245N-{3-[5-(2-amino-4-pyrimidinyl)-2-(tetrahydro-2H-pyran-4-yl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide

Following a procedure analogous to the procedure described in Example52, Step B usingN-{3-[5-(2-chloro-4-pyrimidinyl)-2-(tetrahydro-2H-pyran-4-yl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide(0.150 g, 0.265 mmol) and 7N ammonia in methanol (5.67 mL, 39.7 mmol),the title compound was obtained as a white solid (93 mg, 64% yield). MS(ESI): 548 [M+H]⁺.

Example 2462,5-difluoro-N-{2-fluoro-3-[5-(2-methyl-4-pyrimidinyl)-2-(tetrahydro-2H-pyran-4-yl)-1,3-thiazol-4-yl]phenyl}benzenesulfonamide

Following a procedure analogous to the procedure described in Example 25usingN-{3-[5-(2-chloro-4-pyrimidinyl)-2-(tetrahydro-2H-pyran-4-yl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide(150 mg, 0.265 mmol) and 2N dimethylzinc in toluene ((0.265 mL, 0.529mmol), the title compound was obtained as a solid (116 mg, 73% yield).MS (ESI): 547 [M+H]⁺.

Example 247N-(3-{2-(1,1-dimethylethyl)-5-[2-(3-hydroxypropyl)-4-pyrimidinyl]-1,3-thiazol-4-yl}-2-fluorophenyl)-2,6-difluorobenzenesulfonamide

To a stirring solution of 2-propen-1-ol (0.038 ml, 0.557 mmol) intetrahydrofuran (1 ml) at 0° C. was added 9-BBN (3.34 ml, 1.670 mmol).The reaction mixture taken out of the ice bath and stirred for 2 h andadded a solution ofN-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide(0.15 g, 0.278 mmol), K₂CO₃ (0.742 ml, 2.226 mmol), andbis(tri-t-butylphosphine)palladium (0) (0.014 g, 0.028 mmol) inN,N-dimethylformamide (1 ml) and stirred for 30 minutes. The reactionmixture was heated to 50° C. After 4 h, the reaction was diluted withEtOAc and saturated NH₄Cl. The mixture was extracted 2× with EtOAc,dried over MgSO₄, filtered, and concentrated. The crude mixture wasplaced on silica gel and chromatography (0 to 80% DCM/MeOH, gradient) toobtain the title compound (157 mg, 42%. ¹H NMR (400 MHz, DMSO-d₆) ppm10.88 (s, 1H), 8.47 (d, J=5.49 Hz, 1H), 7.67 (m, 1H), 7.43 (m, 2H), 7.31(t, J=7.78 Hz, 1H), 7.23 (t, J=9.06 Hz, 2H), 6.62 (d, J=5.31 Hz, 1H),4.51 (m, 1H), 3.46 (m, 2H), 2.86 (m, 2H), 1.87 (m, 2H), 1.41 (m, 9H); MS(ESI): 563 [M+H]⁺.

Example 2482,5-difluoro-N-{2-fluoro-3-[5-[2-(3-hydroxy-3-methylbutyl)-4-pyrimidinyl]-2-(4-morpholinyl)-1,3-thiazol-4-yl]phenyl}benzenesulfonamide

Following a procedure analogous to the procedure described in Example247 usingN-{3-[5-(2-chloro-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide(0.2 g, 0.352 mmol) and 2-Methyl-3-buten-2-ol (0.110 ml, 1.056 mmol),the title compound was obtained as a solid (83 mg, 38% yield). ¹H NMR(400 MHz, DMSO-d₆) δ ppm 10.76 (s, 1H), 8.28 (d, J=5.49 Hz, 1H), 7.53(m, 3H), 7.43 (m, 1H), 7.35 (d, J=6.04 Hz, 1H), 7.29 (t, J=7.69 Hz, 1H),6.31 (d, J=5.49 Hz, 1H), 4.28 (s, 1H), 3.71 (m, 4H), 3.50 (m, 4H), 2.81(m, 2H), 1.77 (m, 2H), 1.12 (s, 6H); MS (ESI): 620 [M+H]⁺.

Example 249N-(3-{2-(1,1-dimethylethyl)-5-[2-(3-hydroxy-3-methylbutyl)-4-pyrimidinyl]-1,3-thiazol-4-yl}-2-fluorophenyl)-2,6-difluorobenzenesulfonamide

Following a procedure analogous to the procedure described in Example247 usingN-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide(0.15 g, 0.278 mmol) and 2-Methyl-3-buten-2-ol (0.087 ml, 0.835 mmol),the title compound was obtained as a solid (86 mg, 52% yield). ¹H NMR(400 MHz, DMSO-d₆) ppm 10.88 (s, 1H), 8.47 (dd, J=5.31, 1.46 Hz, 1H),7.67 (m, 1H), 7.43 (m, 2H), 7.31 (t, J=8.15 Hz, 1H), 7.23 (t, J=9.61 Hz,2H), 6.63 (d, J=4.94 Hz, 1H), 4.29 (s, 1H), 2.87 (m, 2H), 1.78 (d,J=8.42 Hz, 2H), 1.43 (d, J=1.46 Hz, 9H), 1.13 (d, J=1.28 Hz, 6H); MS(ESI): 591 [M+H]⁺.

Example 250N-(3-{2-(1,1-dimethylethyl)-5-[2-(3-hydroxy-3-methylbutyl)-4-pyrimidinyl]-1,3-thiazol-4-yl}-2-fluorophenyl)-2,5-difluorobenzenesulfonamide

Following a procedure analogous to the procedure described in Example247 usingN-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide(0.15 g, 0.278 mmol) and 2-methyl-3-buten-2-ol (0.087 ml, 0.835 mmol),the title compound was obtained as a solid (164 mg, 57% yield); ¹H NMR(400 MHz, DMSO-d₆) ppm 10.75 (s, 1H), 8.48 (d, J=5.31 Hz, 1H), 7.55 (m,1H), 7.46 (m, 4H), 7.30 (t, J=8.33 Hz, 1H), 6.64 (d, J=5.31 Hz, 1H),4.29 (s, 1H), 2.87 (m, 2H), 1.76 (m, 2H), 1.42 (s, 9H), 1.12 (s, 6H); MS(ESI): 592 [M+H]⁺.

Example 251N-[3-(2-(1,1-dimethylethyl)-5-{2-[2-(methylsulfonyl)ethyl]-4-pyrimidinyl}-1,3-thiazol-4-yl)-2-fluorophenyl]-2,6-difluorobenzenesulfonamide

Step A:N-{3-[2-(1,1-dimethylethyl)-5-(2-ethenyl-4-pyrimidinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide

N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide(0.421 g, 0.781 mmol), potassium vinyl trifluoroborate (0.262 g, 1.953mmol), PdCl₂(dppf)₂ (0.057 g, 0.078 mmol), and triethylamine (1.089 ml,7.81 mmol) in n-propanol (7.81 ml) were heated at 100° C. in a screw-topvial overnight. The reaction mixture was filtered through celite and thecelite rinsed with EtOAc. The combined organic portions were washed withwater, dried over MgSO₄, filtered and concentrated to dryness. The crudemixture was placed on silica gel and chromatography (0 to 80% DCM/EtOAc,gradient) to obtain the title compound (350 mg, 84%). ¹H NMR (400 MHz,DMSO-d₆) δ ppm 10.88 (s, 1H), 8.56 (d, J=5.31 Hz, 1H), 7.67 (ddd,J=14.28, 8.15, 6.13 Hz, 1H), 7.43 (t, J=7.60 Hz, 2H), 7.31 (t, J=7.69Hz, 1H), 7.22 (t, J=9.25 Hz, 2H), 6.74 (m, 2H), 6.44 (dd, J=17.58, 1.65Hz, 1H), 5.75 (dd, J=10.62, 2.01 Hz, 1H), 1.43 (m, 9H); MS (ESI): 531[M+H]⁺.

Step B:N-[3-(2-(1,1-dimethylethyl)-5-{2-[2-(methylsulfonyl)ethyl]-4-pyrimidinyl}-1,3-thiazol-4-yl)-2-fluorophenyl]-2,6-difluorobenzenesulfonamide

N-{3-[2-(1,1-dimethylethyl)-5-(2-ethenyl-4-pyrimidinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide(0.15 g, 0.283 mmol) and methane sulfinic acid, sodium salt (0.144 g,1.414 mmol) were stirred in acetic acid (1.5 ml) and ethanol (1.5 ml) atRT in a screw-top vial overnight. The reaction mixture is diluted withwater and extracted 2× with EtOAc. The EtOAc is washed with brine, driedover MgSO4, filtered, and concentrated. The crude mixture was placed onsilica gel and chromatography (0 to 80% DCM/EtOAc, gradient) to obtainthe title compound (173 mg, 81%). ¹H NMR (400 MHz, DMSO-d₆) ppm 10.87(s, 1H), 8.54 (d, J=5.31 Hz, 1H), 7.68 (ddd, J=14.56, 8.42, 6.13 Hz,1H), 7.43 (t, J=7.32 Hz, 2H), 7.32 (t, J=7.97 Hz, 1H), 7.23 (t, J=9.06Hz, 2H), 6.75 (d, J=5.31 Hz, 1H), 3.53 (m, 2H), 3.29 (m, 2H), 3.03 (s,3H), 1.44 (m, 9H); MS (ESI): 611 [M+H]⁺.

Example 252N-[2-chloro-3-(2-(1,1-dimethylethyl)-5-{2-[2-(methylsulfonyl)ethyl]-4-pyrimidinyl}-1,3-thiazol-4-yl)phenyl]-2,5-difluorobenzenesulfonamide

Following a procedure analogous to the procedure described in Example251 usingN-{2-chloro-3-[2-(1,1-dimethylethyl)-5-(2-ethenyl-4-pyrimidinyl)-1,3-thiazol-4-yl]phenyl}-2,5-difluorobenzenesulfonamide(0.135 g, 0.247 mmol) and methane sulfinic acid, sodium salt (0.126 g,1.234 mmol), the title compound was obtained as a solid (127 mg, 82%yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.72 (s, 1H), 8.54 (d, J=5.49Hz, 1H), 7.52 (m, 3H), 7.44 (m, 2H), 6.48 (d, J=5.49 Hz, 1H), 3.54 (m,2H), 3.28 (m, 2H), 3.04 (s, 3H), 1.42 (s, 9H); MS (ESI): 627 [M+H]⁺.

Example 253N-{3-[2-(1,1-dioxido-4-thiomorpholinyl)-5-(2-methyl-4-pyrimidinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide

Step A:N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dioxido-4-thiomorpholinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide

Following a procedure analogous to the procedure described inintermediate 9 usingN-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dioxido-4-thiomorpholinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide(1.5 g, 3.40 mmol) and 4-thiomorpholinecarbothioamide 1,1-dioxide (0.792mL, 4.07 mmol), the title compound was obtained as a solid (2.06 mg, 98%yield). MS (ESI): 616 [M+H]⁺.

Step B:N-{3-[2-(1,1-dioxido-4-thiomorpholinyl)-5-(2-methyl-4-pyrimidinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide

Following a procedure analogous to the procedure described in Example 25usingN-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dioxido-4-thiomorpholinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide(200 mg, 0.325 mmol) and 2N dimethylzinc in toluene (0.325 mL, 0.649mmol), the title compound was obtained as a solid (110 mg, 59% yield).MS (ESI): 596 [M+H]⁺.

Example 254N-[3-(2-(1,1-dimethylethyl)-5-{2-[3-(4-morpholinyl)-3-oxopropyl]-4-pyrimidinyl}-1,3-thiazol-4-yl)-2-fluorophenyl]-2,5-difluorobenzenesulfonamide

3-{4-[4-(3-{[(2,5-difluorophenyl)sulfonyl]amino}-2-fluorophenyl)-2-(1,1-dimethylethyl)-1,3-thiazol-5-yl]-2-pyrimidinyl}propanoicacid (200 mg, 0.347 mmol) was taken up in N,N-dimethylformamide (DMF) (2ml). HATU (0.158 g, 0.416), DIEA (0.134 g, 1.041 mmol), and morphiline(0.060 g, 0.694) were added. After 30 min, the reaction mixture wasconcentrated and residue was purified via Gilson Acidic HPLC (10 to 90%gradient, Acetonitrile/H₂O+TFA; C18 column) to obtain the title compound(147 mg, 53%) as white solid. MS (ESI): 646 [M+H]⁺.

Example 255N-[3-(2-(1,1-dimethylethyl)-5-{2-[3-(1,1-dioxido-4-thiomorpholinyl)-3-oxopropyl]-4-pyrimidinyl}-1,3-thiazol-4-yl)-2-fluorophenyl]-2,5-difluorobenzenesulfonamide

Following a procedure analogous to the procedure described in Example254 using3-{4-[4-(3-{[(2,5-difluorophenyl)sulfonyl]amino}-2-fluorophenyl)-2-(1,1-dimethylethyl)-1,3-thiazol-5-yl]-2-pyrimidinyl}propanoicacid (200 mg, 0.347 mmol) and thiomorpholine 1,1-dioxide (0.094 g, 0.694mmol), the title compound was obtained as a white solid (108 mg, 36%yield). MS (ESI): 694 [M+H]⁺.

Example 256N-{3-[2-(1,1-dimethylethyl)-5-(4-pyrimidinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-3-furansulfonamide

Following a procedure analogous to the procedure described in Example 26usingN-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-3-furansulfonamide(77 mg, 0.156 mmol) and ammonium formate (98 mg, 1.562 mmol), the titlecompound was obtained as a yellow solid (23 mg, 30% yield). MS (ESI):459 [M+H]⁺.

Example 257N-{3-[5-(2-amino-4-pyrimidinyl)-2-ethyl-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide

Following a procedure analogous to the procedure described in Example52, Step B usingN-{3-[5-(2-chloro-4-pyrimidinyl)-2-ethyl-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide(100 mg, 0.196 mmol) and ammonium hydroxide (3 mL, 77 mmol), the titlecompound was obtained as an off-white solid (52 mg, 51% yield). MS(ESI): 492 [M+H]⁺.

Example 258N-{3-[5-(2-amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2,4-difluorophenyl}-2,5-difluorobenzenesulfonamide

Following a procedure analogous to the procedure described in Example52, Step B usingN-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2,4-difluorophenyl}-2,5-difluorobenzenesulfonamide(75 mg, 0.135 mmol) and ammonium hydroxide (3 mL), the title compoundwas obtained as an off-white solid (50 mg, 69% yield). MS (ESI): 538[M+H]⁺.

Example 259N-{3-[5-(2-amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-chlorophenyl}-2-furansulfonamide

Following a procedure analogous to the procedure described in Example52, Step B usingN-{2-chloro-3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]phenyl}-2-furansulfonamide(75 mg, 0.147 mmol) and ammonium hydroxide (3 mL), the title compoundwas obtained as an off-white solid (49 mg, 68% yield). MS (ESI): 490[M+H]⁺.

Example 260N-{3-[2-(1,1-dimethylethyl)-5-(4-pyrimidinyl)-1,3-thiazol-4-yl]-2,4-difluorophenyl}-2,5-difluorobenzenesulfonamide

Following a procedure analogous to the procedure described in Example 26usingN-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2,4-difluorophenyl}-2,5-difluorobenzenesulfonamide(75 mg, 0.135 mmol) and ammonium formate (85 mg, 1.347 mmol), the titlecompound was obtained as a yellow solid (21 mg, 29% yield). MS (ESI):523 [M+H]⁺.

Example 261N-{2-chloro-3-[2-(1,1-dimethylethyl)-5-(4-pyrimidinyl)-1,3-thiazol-4-yl]phenyl}-2-furansulfonamide

Following a procedure analogous to the procedure described in Example 26usingN-{2-chloro-3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]phenyl}-2-furansulfonamide(75 mg, 0.147 mmol) and ammonium formate (93 mg, 1.47 mmol), the titlecompound was obtained as a yellow solid (23 mg, 34% yield). MS (ESI):475 [M+H]⁺.

Example 262N-{3-[2-(1,1-dimethylethyl)-5-(2-methyl-4-pyrimidinyl)-1,3-thiazol-4-yl]-2,4-difluorophenyl}-2,5-difluorobenzenesulfonamide

Following a procedure analogous to the procedure described in Example 25usingN-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2,4-difluorophenyl}-2,5-difluorobenzenesulfonamide(150 mg, 0.269 mmol) and dimethyl zinc in toluene (0.269 mL, 0.539mmol), the title compound was obtained as a yellow solid (105 mg, 72%yield). MS (ESI): 537 [M+H]⁺.

Example 263N-{2-chloro-3-[2-(1,1-dimethylethyl)-5-(2-methyl-4-pyrimidinyl)-1,3-thiazol-4-yl]phenyl}-2-furansulfonamide

Following a procedure analogous to the procedure described in Example 25usingN-{2-chloro-3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]phenyl}-2-furansulfonamide(150 mg, 0.294 mmol) and dimethyl zinc in toluene (0.294 mL, 0.589mmol), the title compound was obtained as a yellow solid (113 mg, 78%yield). MS (ESI): 489 [M+H]⁺.

Example 264N-{3-[5-(2-amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-chlorophenyl}-3-furansulfonamide

Following a procedure analogous to the procedure described in Example52, Step B usingN-{2-chloro-3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]phenyl}-3-furansulfonamide(130 mg, 0.255 mmol) and ammonium hydroxide (3 mL), the title compoundwas obtained as an off-white solid (48 mg, 38% yield). MS (ESI): 490[M+H]⁺.

Example 265N-{3-[5-(2-amino-4-pyrimidinyl)-2-(tetrahydro-2H-pyran-4-yl)-1,3-thiazol-4-yl]-2-chlorophenyl}-3-furansulfonamide

Following a procedure analogous to the procedure described in Example52, Step B usingN-{2-chloro-3-[5-(2-chloro-4-pyrimidinyl)-2-(tetrahydro-2H-pyran-4-yl)-1,3-thiazol-4-yl]phenyl}-3-furansulfonamide(95 mg, 0.177 mmol) and ammonium hydroxide (4 mL), the title compoundwas obtained as an off-white solid (59 mg, 61% yield). MS (ESI): 519[M+H]⁺.

Example 266N-{3-[5-(2-amino-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]-2-chlorophenyl}-3-furansulfonamide

Following a procedure analogous to the procedure described in Example52, Step B usingN-{2-chloro-3-[5-(2-chloro-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]phenyl}-3-furansulfonamide(114 mg, 0.212 mmol) and ammonium hydroxide (4 mL) and 1,4-Dioxane (1mL), the title compound was obtained as an off-white solid (82 mg, 70%yield). MS (ESI): 519 [M+H]⁺.

Example 267N-{3-[5-(2-amino-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-3-furansulfonamide

Following a procedure analogous to the procedure described in Example52, Step B usingN-{3-[5-(2-chloro-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-3-furansulfonamide(100 mg, 0.192 mmol) and ammonium hydroxide (4 mL) and 1,4-Dioxane (1mL), the title compound was obtained as an off-white solid (65 mg, 64%yield). MS (ESI): 503 [M+H]⁺.

Example 268N-{2-chloro-3-[2-(1,1-dimethylethyl)-5-(4-pyrimidinyl)-1,3-thiazol-4-yl]phenyl}-3-furansulfonamide

Following a procedure analogous to the procedure described in Example 26usingN-{2-chloro-3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]phenyl}-3-furansulfonamide(130 mg, 0.255 mmol) and ammonium formate (161 mg, 2.55 mmol), the titlecompound was obtained as a white solid (50 mg, 39% yield). MS (ESI): 474[M+H]⁺.

Example 269N-{2-chloro-3-[2-(4-morpholinyl)-5-(4-pyrimidinyl)-1,3-thiazol-4-yl]phenyl}-3-furansulfonamide

Following a procedure analogous to the procedure described in Example 26usingN-{2-chloro-3-[5-(2-chloro-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]phenyl}-3-furansulfonamide(114 mg, 0.212 mmol) and ammonium formate (134 mg, 2.11 mmol), the titlecompound was obtained as a white solid (33 mg, 29% yield). MS (ESI): 503[M+H]⁺.

Example 270N-{2-chloro-3-[2-(1,1-dimethylethyl)-5-(2-methyl-4-pyrimidinyl)-1,3-thiazol-4-yl]phenyl}-3-furansulfonamide

Following a procedure analogous to the procedure described in Example 25usingN-{2-chloro-3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]phenyl}-3-furansulfonamide(130 mg, 0.255 mmol) and dimethyl zinc in toluene (0.255 mL, 0.510mmol), the title compound was obtained as a solid (35 mg, 26% yield). MS(ESI): 489 [M+H]⁺.

Example 271N-{2-chloro-3-[5-(2-methyl-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]phenyl}-3-furansulfonamide

Following a procedure analogous to the procedure described in Example 25usingN-{2-chloro-3-[5-(2-chloro-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]phenyl}-3-furansulfonamide(115 mg, 0.214 mmol) and dimethyl zinc in toluene (0.214 mL, 0.427mmol), the title compound was obtained as a solid (60 mg, 51% yield). MS(ESI): 519 [M+H]⁺.

Example 272N-{2-fluoro-3-[5-(2-methyl-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]phenyl}-3-furansulfonamide

Following a procedure analogous to the procedure described in Example 25usingN-{3-[5-(2-chloro-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-3-furansulfonamide(100 mg, 0.192 mmol) and dimethyl zinc in toluene (0.192 mL, 0.383mmol), the title compound was obtained as a solid (50 mg, 49% yield). MS(ESI): 502 [M+H]⁺.

Example 2732,5-difluoro-N-{2-fluoro-3-[5-(2-{[(methylsulfonyl)amino]methyl}-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]phenyl}benzenesulfonamide

Step A:N-{3-[5-(2-cyano-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide

N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide(3.54 g, 6.23 mmol), zinc cyanide (0.805 g, 6.86 mmol), andtetrakis(triphenylphosphine)palladium (0) (0.720 g, 0.623 mmol) werestirred in N,N-dimethylformamide (DMF) (27.1 ml) overnight at 80° C. Thereaction mixture was added dropwise into water to give a solid. Thesolids were filtered and dried in a vacuum oven overnight. DCM and MeOH(5:1) were added to solid and heat at 60° C. The mixture was cooled andfiltered to obtainN-{3-[5-(2-cyano-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide(2.06, 60%). MS (ESI): 559 [M+H]⁺.

Step B:N-{3-[5-[2-(aminomethyl)-4-pyrimidinyl]-2-(4-morpholinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide

To a suspension ofN-{3-[5-(2-cyano-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide(2.12 g, 3.80 mmol) in dichloromethane (DCM) (38.0 ml) at −78° C. wasadded DIBAL-H (18.98 ml, 18.98 mmol). The yellow suspension was slowlywarmed to RT and stirred 1 hr. The reaction was quenched with Rochelle'ssalts and stirred about 1 hr. 4N HCl was added to clear the emulsion.The HCl solution was extracted with DCM (3×). The aqueous was passedthrough celite and neutralize with 6N NaOH. Solid formed duringneutralizing and was filtered to obtainN-{3-[5-[2-(aminomethyl)-4-pyrimidinyl]-2-(4-morpholinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide(1.57 g, 73%). MS (ESI): 563 [M+H]⁺.

Step C:2,5-difluoro-N-{2-fluoro-3-[5-(2-{[(methylsulfonyl)amino]methyl}-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]phenyl}benzenesulfonamide

To a suspension ofN-{3-[5-[2-(aminomethyl)-4-pyrimidinyl]-2-(4-morpholinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide(0.1 g, 0.178 mmol) in dichloromethane (0.500 ml) was added pyridine(0.036 ml, 0.444 mmol) and a solution of methane sulphonyl chloride(0.025 g, 0.222 mmol) in dichloromethane (0.2 ml) and stirred overnight.The reaction was concentrated. The crude product was added to a silicagel column and eluted with DCM with MeOH (0% to 10%) and collectedfractions to obtain crude product. The crude product was treated withEtOAc and hexanes and sonicated to form a white solid. The solid wasfiltered to obtain2,5-difluoro-N-{2-fluoro-3-[5-(2-{[(methylsulfonyl)amino]methyl}-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]phenyl}benzenesulfonamide(38 mg, 33%) as white solid. MS (ESI): 641 [M+H]⁺.

Example 274N-({4-[4-(3-{[(2,5-difluorophenyl)sulfonyl]amino}-2-fluorophenyl)-2-(4-morpholinyl)-1,3-thiazol-5-yl]-2-pyrimidinyl}methyl)cyclopentanecarboxamide

To a suspension ofN-{3-[5-[2-(aminomethyl)-4-pyrimidinyl]-2-(4-morpholinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide(0.1 g, 0.178 mmol) in dichloromethane (1.270 ml) was addedtriethylamine (0.062 ml, 0.444 mmol). A solution of cyclopentanecarbonylchloride (0.024 g, 0.178 mmol) in dichloromethane (0.508 ml) was addeddropwise and stirred. The reaction was quenched with water, extracted 2×with DCM, the organic extracts dried over MgSO₄, filtered, andconcentrated. The crude product was added to a silica gel column andeluted with DCM with MeOH (0% to 10%) and collected fractions to obtainthe title compound as a solid (30 mg, 25% yield). MS (ESI): 659 [M+H]⁺.

Example 275N-({4-[4-(3-{[(2,5-difluorophenyl)sulfonyl]amino}-2-fluorophenyl)-2-(4-morpholinyl)-1,3-thiazol-5-yl]-2-pyrimidinyl}methyl)-2-methylpropanamide

To suspension ofN-{3-[5-[2-(aminomethyl)-4-pyrimidinyl]-2-(4-morpholinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide(0.1 g, 0.178 mmol) in dichloromethane (1.778 ml) was added HATU (0.084g, 0.222 mmol) and 2-methylpropanoic acid (0.047 g, 0.533 mmol). Thereaction mixture was stirred and heated at 55° C. After 16 h, thereaction mixture was quenched with water, extracted with DCM (2×), driedover MgSO₄, filtered, and concentrated. The crude product was added to asilica gel column and eluted with DCM with 10% MeOH in DCM (5% to 40%)and collected fractions to obtain the title compound as a solid (48 mg,42% yield). MS (ESI): 633 [M+H]⁺.

Example 276N-({4-[4-(3-{[(2,5-difluorophenyl)sulfonyl]amino}-2-fluorophenyl)-2-(4-morpholinyl)-1,3-thiazol-5-yl]-2-pyrimidinyl}methyl)acetamide

Following a procedure analogous to the procedure described in Example275 usingN-{3-[5-[2-(aminomethyl)-4-pyrimidinyl]-2-(4-morpholinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide(0.1 g, 0.178 mmol) and acetic acid (0.053 g, 0.889 mmol), the titlecompound was obtained as a solid (30 mg, 27% yield). MS (ESI): 605[M+H]⁺.

Example 277N-{3-[5-(2-ethenyl-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide

Following a procedure analogous to the procedure described in Example251 usingN-{3-[5-(2-chloro-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide(0.82 g, 1.444 mmol) and potassium vinyl trifluoroborate (0.483 g, 3.61mmol), the title compound was obtained as a solid (481 mg, 59% yield).MS (ESI): 588 [M−H]⁻.

Example 278N-{3-[5-(2-amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2-pyridinesulfonamide

To a suspension of sodium 2-pyridinesulfinate (48.4 mg, 0.291 mmol) indichloromethane (3 ml) was added N-chlorosuccinimide (38.9 mg, 0.291mmol). After 1 hour, the reaction mixture was filtered through a shortCelite plug. To the crude sulfonyl chloride solution was added the4-[4-(3-amino-2-fluorophenyl)-2-(1,1-dimethylethyl)-1,3-thiazol-5-yl]-2-pyrimidinamine(50 mg, 0.146 mmol) and pyridine (0.035 ml, 0.437 mmol), and the mixturewas stirred for 3 hours at ambient temperature. After 3 hours, thereaction was quenched with methanol, and the crude reaction mixture wasconcentrated, redissolved in methanol, and purified via reversed-phaseHPLC chromatography, eluting with 30-60% acetonitrile/0.1% aqueoustrifluoroacetic acid. The desired fractions were combined, neutralizedwith aqueous saturated sodium bicarbonate, and extracted with ethylacetate. The organic layer was washed with brine, dried over anhydroussodium sulfate, filtered, and concentrated to obtain the title compound(8.8 mg, 12%) as tan solid. MS (ESI): 485 [M+H]⁺.

Example 279N-{3-[5-(2-amino-4-pyrimidinyl)-2-(tetrahydro-2H-pyran-4-yl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2-pyridinesulfonamide

Following a procedure analogous to the procedure described in Example278 using4-[4-(3-amino-2-fluorophenyl)-2-(tetrahydro-2H-pyran-4-yl)-1,3-thiazol-5-yl]-2-pyrimidinamine(100 mg, 0.269 mmol) and sodium 2-pyridinesulfinate (224 mg, 1.346mmol), the title compound was obtained as a yellow solid (58 mg, 42%yield). MS (ESI): 513 [M−H]⁺.

Example 280N-{3-[5-(2-amino-4-pyrimidinyl)-2-(tetrahydro-2H-pyran-4-yl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2-pyrazinesulfonamide

Following a procedure analogous to the procedure described in Example278 using4-[4-(3-amino-2-fluorophenyl)-2-(tetrahydro-2H-pyran-4-yl)-1,3-thiazol-5-yl]-2-pyrimidinamine(100 mg, 0.269 mmol) and sodium 2-pyrazinesulfinate (135 mg, 0.808mmol), the title compound was obtained as a yellow solid (30 mg, 21%yield). MS (ESI): 514 [M−H]⁺.

Example 281N-{3-[5-(2-amino-4-pyrimidinyl)-2-(tetrahydro-2H-pyran-4-yl)-1,3-thiazol-4-yl]-2-fluorophenyl}-3-furansulfonamide

Following a procedure analogous to the procedure described in Example52, Step B usingN-{3-[5-(2-chloro-4-pyrimidinyl)-2-(tetrahydro-2H-pyran-4-yl)-1,3-thiazol-4-yl]-2-fluorophenyl}-3-furansulfonamide(1.03 g×3, 5.95 mmol) and ammonium hydroxide (15 mL), the title compoundwas obtained as a white solid (1.86 g, 61% yield). MS (ESI): 502 [M+H]⁺.

Example 282N-{3-[5-(2-amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-1-methyl-1H-pyrazole-5-sulfonamidehydrochloride

N-{3-[5-(2-Chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-1-methyl-1H-pyrazole-5-sulfonamide(530 mg, 1.04 mmol) and ammonium hydroxide (26%, 15 ml) was heated in asteel reactor to 100° C. for 3 h. The reaction mixture was cooled andconcentrated under reduced pressure, the residue was dissolved inmethanol, and purified by Pre-HPLC (A=10 m MNH₄HCO₃/H₂O,B=Acetonitrile), then the white solid obtained was dissolved in EtOAc,treated with HCl (g) for 30 min. The mixture was concentrated underreduced pressure, and then the residue was suspended in ether (20 ml),treated with ultrasonic for 3 min, filtered, the solid was suspended inether (20 ml) again, treated with ultrasonic for 3 min, filtered toafford the title compound was obtained as a white solid (142 mg, 26%).¹HNMR (MEOD-d⁴): δ ppm 8.05 (br s, 1H), 7.61-7.65 (ddd, J₁=7.7 Hz,J₂=1.6 Hz, 1H), 7.42-7.46 (m, 2H), 7.32-7.36 (t, J=8.0 Hz, 1H),6.70-6.71 (d, J=2.0 Hz, 1H), 6.25-6.27 (d, J=6.4 Hz, 1H), 4.04 (s, 3H),1.50 (s, 9H). MS: 488.2 [M⁺H]⁺.

Example 283N-{3-[5-(2-amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-1-methyl-1H-pyrazole-4-sulfonamidehydrochloride

Following a procedure analogous to the procedure described in Example282 usingN-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-1-methyl-1H-pyrazole-4-sulfonamide(750 mg, 1.47 mmol) and ammonium hydroxide (12 ml), the title compoundwas obtained as a white solid (183 mg, 23%). ¹HNMR (DMSO-d⁶): δ ppm10.13 (s, 1H), 8.23 (s, 1H), 8.11 (br s, 1.5H), 7.68 (s, 1.5H),7.46-7.49 (dd, J₁=7.6 Hz, J₂=0.8 Hz, 1H), 7.35 (br s, 1H), 7.27-7.31 (t,J=8.0 Hz, 1H), 6.06 (br s, 2H), 3.82 (s, 3H), 1.42 (s, 9H); MS: 488[M⁺H]⁺.

Example 284N-{3-[5-(2-amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-1-methyl-1H-pyrrole-3-sulfonamidehydrochloride

Following a procedure analogous to the procedure described in Example282 usingN-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-1-methyl-1H-pyrrole-3-sulfonamide(230 mg, 0.45 mmol) and ammonium hydroxide (5 ml), the title compoundwas obtained as a white solid (130 mg, 54.8%). ¹HNMR (DMSO-d⁶): δ ppm9.80 (s, 1H), 8.13-8.15 (d, J=5.6 Hz, 1H), 7.87 (br s, 2H), 7.47-7.51(dd, J₁=7.6 Hz, J₂=2.0 Hz, 1H), 7.23-7.29 (m, 3H), 6.80-6.82 (t, J=2.4Hz, 1H), 6.23-6.24 (dd, J₁=2.0H, J₂=2.8 Hz, 1H), 6.13-6.14 (d, J=6.0 Hz,1H), 3.61 (s, 3H), 1.42 (s, 9H); MS: 487.1 [M⁺H]⁺.

Example 285N-{3-[5-(2-amino-4-pyrimidinyl)-2-(tetrahydro-2H-pyran-4-yl)-1,3-thiazol-4-yl]-2-fluorophenyl}-1-methyl-1H-pyrrole-3-sulfonamidehydrochloride

Following a procedure analogous to the procedure described in Example282 usingN-{3-[5-(2-chloro-4-pyrimidinyl)-2-(tetrahydro-2H-pyran-4-yl)-1,3-thiazol-4-yl]-2-fluorophenyl}-1-methyl-1H-pyrrole-3-sulfonamide(260 mg, 0.487 mmol) and ammonium hydroxide (10 ml), the title compoundwas obtained as a white solid (132 mg, 49.2%). ¹HNMR (MEOD-d⁴): δ ppm7.92-7.93 (d, J=6.4 Hz, 1H), 7.50-7.54 (t, J=7.6 Hz, 1H), 7.16-7.23 (m,2H), 7.12 (s, 1H), 6.31-6.64 (t, J=2.4 Hz, 1H), 6.30-6.32 (d, J=6.0 Hz,1H), 6.23 (s, 1H), 3.94-3.97 (dd, J₁=11.4 Hz, J₂=2.4 Hz, 2H), 3.57 (s,3H), 3.47-3.53 (t, J₁=11.4 Hz, 2H), 3.26-3.28 (m, 1H), 1.98-2.01 (dd,J₁=11.8 Hz, J₂=1.2 Hz, 2H), 1.76-1.86 (dd, J₁=12.1 Hz, J₂=4.4 Hz, 2H);MS: 515.2 [M⁺H]⁺.

Example 286N-{3-[5-(2-amino-4-pyrimidinyl)-2-(tetrahydro-2H-pyran-4-yl)-1,3-thiazol-4-yl]-2-fluorophenyl}-1-methyl-1H-pyrazole-4-sulfonamidehydrochloride

Following a procedure analogous to the procedure described in Example282 usingN-{3-[5-(2-chloro-4-pyrimidinyl)-2-(tetrahydro-2H-pyran-4-yl)-1,3-thiazol-4-yl]-2-fluorophenyl}-1-methyl-1H-pyrazole-4-sulfonamide(720 mg, 1.34 mmol) and ammonium hydroxide (15 ml), the title compoundwas obtained as a white solid (122 mg, 16%). ¹HNMR (MEOD-d⁴): δ ppm7.95-7.97 (d, J=8.0 Hz, 2H), 7.52-7.56 (m, 2H), 7.29-7.32 (t, J=6.0 Hz,1H), 7.21-7.25 (t, J=8.0 Hz, 1H), 6.32-6.33 (d, J=6.4 Hz, 1H), 3.92-3.96(dd, J₁=11.8 Hz, J₂=3.2 Hz, 2H), 3.77 (s, 3H), 3.45-3.51 (dd, J₁=11.4Hz, J₂=1.2 Hz, 2H), 3.23-3.31 (m, 1H), 1.97-1.99 (d, J=11.2 Hz, 2H),1.75-1.85 (dd, J₁=12.2 Hz, J₂=4.0 Hz, 2H); MS: 516 [M⁺H]⁺.

Example 287N-{3-[5-(2-amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-1-methyl-1H-imidazole-2-sulfonamidehydrochloride

Following a procedure analogous to the procedure described in Example282 usingN-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-1-methyl-1H-imidazole-2-sulfonamide(560 mg, 1.10 mmol) and ammonium hydroxide (15 ml), the title compoundwas obtained as a white solid (156 mg, 27%). ¹HNMR (MEOD-d⁴): δ ppm 8.06(br s, 1H), 7.66 (s, 1H), 7.53-7.58 (m, 2H), 7.44 (s, 1H), 7.36-7.40 (t,J=8.0 Hz, 1H), 6.47-6.51 (m, 1H), 4.06 (s, 3H), 1.50 (s, 9H). MS: 488[M⁺H]⁺.

Example 288N-{3-[5-(2-amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-1-methyl-1H-pyrazole-3-sulfonamidehydrochloride

Following a procedure analogous to the procedure described in Example282 usingN-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-1-methyl-1H-pyrazole-3-sulfonamide(760 mg, 1.50 mmol) and ammonium hydroxide (15 ml), the title compoundwas obtained as a white solid (130 mg, 54%). ¹HNMR (MEOD-d⁴): δ ppm7.94-7.96 (d, J=6.4 Hz, 1H), 7.60-7.60 (d, J=2.4 Hz, 1H), 7.44-7.49 (dd,J₁=7.7 Hz, J₂=1.2 Hz, 1H), 7.27-7.30 (t, J=6.4 Hz, 1H), 7.15-7.19 (t,J=8.0 Hz, 1H), 6.56-6.56 (t, J=2.4 Hz, 1H), 6.41-6.43 (d, J=6.8 Hz, 1H),3.81 (s, 3H), 1.39 (s, 9H); MS: 488 [M⁺H]⁺:

Example 289N-{3-[5-(2-amino-4-pyrimidinyl)-2-(tetrahydro-2H-pyran-4-yl)-1,3-thiazol-4-yl]-2-fluorophenyl}-1-methyl-1H-pyrazole-3-sulfonamidehydrochloride

Following a procedure analogous to the procedure described in Example282 usingN-{3-[5-(2-chloro-4-pyrimidinyl)-2-(tetrahydro-2H-pyran-4-yl)-1,3-thiazol-4-yl]-2-fluorophenyl}-1-methyl-1H-pyrazole-3-sulfonamide(640 mg, 1.19 mmol) and ammonium hydroxide (15 ml), the title compoundwas obtained as a white solid (340 mg, 51.5%). ¹HNMR (MEOD-d⁴): δ ppm7.93-7.95 (d, J=6.0 Hz, 1H), 7.59-7.59 (d, J=2.0 Hz, 1H), 7.46-7.50 (dd,J₁=7.8 Hz, J₂=1.6 Hz, 1H), 7.24-7.28 (dd, J₁=6.8 Hz, J₂=1.6 Hz, 1H),7.15-7.18 (t, J=7.8 Hz, 1H), 6.54-6.55 (d, J=2.4 Hz, 1H), 6.32-6.34 (d,J=6.0 Hz, 1H), 3.92-3.96 (dd, J₁=11.6 Hz, J₂=2.4 Hz, 1H), 3.80 (s, 3H),3.45-3.51 (dd, J₁=11.6 Hz, J₂=2.0 Hz, 2H), 3.21-3.28 (m, 1H), 1.96-2.00(dd, J₁=12.8 Hz, J₂=2.4 Hz, 2H), 1.75-1.85 (dd, J₁=12.2 Hz, J₂=4.4 Hz,2H); MS: 516 [M⁺H]⁺.

Example 290N-{3-[2-(1,1-dimethylethyl)-5-(2-{[(2R)-2-hydroxypropyl]amino}-4-pyrimidinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide

A 5 mL microwave tube was charged withN-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide(250 mg, 0.464 mmol) and (R)-(−)-1 amino-2-propanol (348 mg, 4.64 mmol)in toluene (3 mL) to give a colorless solution at rt under nitrogen. Thesealed reaction mixture was microwaved at 90° C. for 30 min. Thereaction mixture was concentrated. The residue was chromatographed onsilica gel column and eluted with CH₂Cl₂ withchloroform/methanol/ammonium hydroxide (90:9:1) (5% to 75%) andcollected fractions to obtain ammonium salt of the product. The ammoniumsalt was diluted with ethyl acetate (10 mL) and water (10 mL) andstirred. 1N HCl was added until pH=6. After stirring, the EtOAc layerwas separated form the water layer. The EtOAc layer was dried overNa₂SO₄, filtered, and concentrated to obtainN-{3-[2-(1,1-dimethylethyl)-5-(2-{[(2R)-2-hydroxypropyl]amino}-4-pyrimidinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide(180 mg, 65.8% yield). MS (ESI): 578 [M+H]⁺.

Example 291N-{3-[2-(1,1-dimethylethyl)-5-(2-{[(2S)-2-hydroxypropyl]amino}-4-pyrimidinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide

Following a procedure analogous to the procedure described in Example291 usingN-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide(250 mg, 0.464 mmol) and (S)-(+)-1-amino-2-propanol (348 mg, 4.64 mmol),the title compound was obtained as an off white solid (40 mg, 14%). MS(ESI): 578 [M+H]⁺.

Example 292N-{3-[5-{2-[(2-cyanoethyl)amino]-4-pyrimidinyl}-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide

A 5 mL microwave tube was charged withN-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide(250 mg, 0.464 mmol) and 3-aminopropionitrile (163 mg, 2.319 mmol) andCsF (70.5 mg, 0.464 mmol) in dimethyl sulfoxide (3.00 mL) to give ayellow solution at rt under nitrogen. The sealed reaction mixture wasmicrowaved at 90° C. for 30 min. For second time, the sealed reactionmixture was microwaved at 100° C. for 1 h. The reaction was diluted withwater and a white solid formed. The reaction was filtered and washedwith water. The crude product was chromatographed on silica gel columnand eluted with CH₂Cl₂ with chloroform/methanol/ammonium hydroxide(90:9:1) (5% to 100%) and collected fractions. Water and DCM were addedto solid and take to a pH=6 and extracted with DCM (3×). The CH₂Cl₂layers were dried over Na₂SO₄, filtered, and concentrated to obtainN-{3-[5-{2-[(2-cyanoethyl)amino]-4-pyrimidinyl}-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide(35 mg, 12%). MS (ESI): 573 [M+H]⁺.

Example 293N-[3-(2-(1,1-dimethylethyl)-5-{2-[(2-hydroxyethyl)amino]-4-pyrimidinyl}-1,3-thiazol-4-yl)-2-fluorophenyl]-2,6-difluorobenzenesulfonamide

Following a procedure analogous to the procedure described in Example290 usingN-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide(250 mg, 0.464 mmol) and 2-aminoethanol (142 mg, 2.31 mmol), the titlecompound was obtained as a white solid (110 mg, 39%). MS (ESI): 564[M+H]⁺.

Example 294N-{3-[5-[2-(cyclopropylamino)-4-pyrimidinyl]-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide

Following a procedure analogous to the procedure described in Example290 usingN-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide(250 mg, 0.464 mmol) and cyclopropylamine (0.163 mL, 2.31 mmol), thetitle compound was obtained as a white solid (40 mg, 14%). MS (ESI): 560[M+H]⁺.

Example 295N-{3-[5-(2-amino-4-pyrimidinyl)-2-(2-hydroxy-1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide

Step A: 3-Hydroxy-2,2-dimethylpropanethioamide

1M-tert-Butylammonium fluoride (2 mL of 1M) in THF was added to asuspension of3-{[(1,1-dimethylethyl)(diphenyl)silyl]oxy}-2,2-dimethylpropanamide(prepared according to Eur. J. Org. Chem., 2007, 934) (150 mg, 0.404mmol) in THF (2 mL) at ambient temperature. The mixture was heated toeffect dissolution of all solids and the solution stirred at ambienttemperature for 1 hour. The solvent was evaporated and residuepartitioned between EtOAc (50 mL) and water (25 mL). The separatedorganic phase was dried (MgSO₄), filtered and filtrate evaporated to aclear gum which was flash chromatographed to give the title compound asa white solid (49 mg, 89%). ¹H NMR (400 MHz, DMSO-d6) δ ppm 9.50 (br s,1H), 8.70 (br s, 1H), 4.86 (t, J=14 Hz, 1H), 3.45 (d, J=14 Hz), 1.42 (s,6H). MS (ESI) 134.1 [M+H]⁺.

Step B:N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(2-hydroxy-1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide

Following a procedure analogous to the procedure described forIntermediate 9 usingN-{3-[(2-chloro-4-pyrimidinyl)acetyl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide(750 mg, 1.7 mmol), NBS (317 mg, 1.782 mmol), and3-hydroxy-2,2-dimethylpropanethioamide (248 mg, 1.86 mmol), the titlecompound was obtained as an yellow foam (460 mg, 45%). A portion of thesample was crystallized from ethyl acetate-hexanes. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 10.92 (s, 1H) 8.54 (d, J=5.31 Hz, 1H) 7.64-7.74 (m, 1H)7.41-7.50 (m, 2H) 7.31-7.36 (m, 1H) 7.24 (t, J=8.97 Hz, 2H) 6.87 (d,J=5.31 Hz, 1H) 5.2-5.4 (br s, 1H) 3.54 (s, 2H) 1.36 (s, 6H). MS (ESI):555.0 [M+H]⁺.

Step C:N-{3-[5-(2-amino-4-pyrimidinyl)-2-(2-hydroxy-1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide

N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(2-hydroxy-1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide(450 mg, 0.811 mmol) and saturated aqueous ammonium hydroxide (6.0 mL)were heated in a microwave reactor to 90° C. for 90 minutes. Thereaction mixture was diluted with water, solution layered with ethylacetate and pH of the mixture adjusted to 7 giving a gummy residue. Theliquors were decanted and set aside; the gum was dissolved in mixture ofwarm ethyl acetate, dichloromethane and methanol and the solution addedto the earlier liquors. The pH of this mixture was re-adjusted to 7.0.Organic phase was separated, dried (MgSO₄), filtered and evaporated togive an orange colored foam which was dissolved in ethyl acetate (5 mL).Drop-wise addition of this solution to rapidly stirring hexanes (100 mL)gave a creamy white suspension which was filtered, filter pad washedwith fresh hexanes, then air-dried to afford the title compound as alight yellow solid (370 mg, 81% yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm10.88 (s, 1H) 7.97 (d, J=5.05 Hz, 1H) 7.64-7.77 (m, 1H) 7.40-7.48 (m,1H) 7.33-7.39 (m, 1H) 7.18-7.32 (m, 4H) 6.75 (s, 2H) 5.84 (d, J=5.05 Hz,1H) 5.09 (t, J=5.43 Hz, 1H) 3.51 (d, J=5.31 Hz, 2H) 1.33 (s, 6H). MS(ESI): 536.0 [M+H]⁺.

Example 296N-{3-[5-(2-amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-oxazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide

Step A: 2-propen-1-yl{3-[bromo(2-chloro-4-pyrimidinyl)acetyl]-2-fluorophenyl}carbamate

To a stirring mixture of 2-propen-1-yl{3-[(2-chloro-4-pyrimidinyl)acetyl]-2-fluorophenyl}carbamate (5 g, 14.30mmol) in DMA (100 ml) was added NBS (2.54 g, 14.30 mmol) and mixture wasstirred at 25° C. overnight. The reaction mixture was poured into water(400 ml) and extracted with EtOAc (100 ml×3). The combined organiclayers were dried over Na₂SO₄ and evaporated to afford the titlecompound as a yellow oil (6.1 g, 99%). MS (ES): 427 [M+H]⁺.

Step B: 2-propen-1-yl{3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-oxazol-4-yl]-2-fluorophenyl}carbamate

A stirring mixture of 2-propen-1-yl{3-[bromo(2-chloro-4-pyrimidinyl)acetyl]-2-fluorophenyl}carbamate (6.1g, 14.23 mmol) and 2,2-dimethylpropanamide (2.16 g, 21.35 mmol) in DMA(200 ml) was heated to 80° C. for 2 days. Upon cooling, the reactionmixture was poured into water (500 ml) and extracted with EtOAc (100ml×5). The combined organic layers were washed with brine, separated,dried over Na₂SO₄, filtered, and concentrated. The crude product wasadded to a silica gel column and eluted with petroleum ether with EtOAc(10% to 16%) and collected fractions to obtain title compound as yellowsolid (1.21 g, 19%). MS (ES): 431 [M+H]⁺.

Step C:3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-oxazol-4-yl]-2-fluoroaniline

Following a procedure analogous to the procedure described inIntermediate 13 using 2-propen-1-yl{3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-oxazol-4-yl]-2-fluorophenyl}carbamate(1.2 g, 2.78 mmol) and tri-n-butyltin hydride (1.21 g, 4.17 mmol), thetitle compound was obtained as a yellow solid (530 mg, 55%). MS (ESI):347 [M+H]⁺.

Step D:N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-oxazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide

Following a procedure analogous to the procedure described inIntermediate 14 using3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-oxazol-4-yl]-2-fluoroaniline(150 mg, 0.433 mmol) and 2,6-difluorobenzenesulfonyl chloride (184 mg,0.865 mmol), the title compound was obtained as a white solid (135 mg,59%). MS (ES): 522 [M+H]⁺.

Step E:N-{3-[5-(2-amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-oxazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide

Following a procedure analogous to the procedure described in Example52, Step B usingN-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-oxazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide(94 mg, 0.179 mmol) and ammonium hydroxide (5 mL), the title compoundwas obtained as a white solid (30 mg, 33%). ¹H-NMR (DMSO-d6): δ ppm10.34 (br s, 1H), 8.18-8.19 (d, J=5.2 Hz, 1H), 7.65 (br s, 1H),7.30-7.34 (t, J=7.4 Hz, 2H), 7.21-7.24 (m, 3H), 6.56 (br s, 2H), 6.45(d, J=5.2 Hz, 1H), 1.40 (s, 9H); MS: 504 [M⁺H]⁺.

Example 297N-{3-[5-(2-amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-oxazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide

Following a procedure analogous to the procedure described in Example52, Step B usingN-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-oxazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide(135 mg, 0.258 mmol) and ammonium hydroxide (5 mL), the title compoundwas obtained as an off-white solid (75 mg, 58%). ¹H-NMR (DMSO-d6): δ ppm10.74 (br s, 1H), 8.26 (d, J=5.6 Hz, 1H), 7.45-7.61 (m, 4H), 7.28-7.37(m, 1H), 6.63-7.26 (m, 1H), 6.62 (d, J=5.6 Hz, 1H), 1.40 (s, 9H); MS:504 [M⁺H]⁺.

Example 298N-{3-[5-(2-amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-oxazol-4-yl]-2-fluorophenyl}-2-furansulfonamide

Following a procedure analogous to the procedure described in Example52, Step B usingN-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-oxazol-4-yl]-2-fluorophenyl}-2-furansulfonamide(72 mg, 0.151 mmol) and ammonium hydroxide (5 mL), the title compoundwas obtained as a white solid (62 mg, 89%). ¹H-NMR (DMSO-d6): δ ppm10.57 (br s, 1H), 8.26 (d, J=5.6 Hz, 1H), 7.97 (m, 1H), 7.44-7.48 (m,1H), 7.23-7.32 (m, 2H), 7.08 (m, 1H), 6.63 (m, 1H) 6.57 (d, J=5.2 Hz,1H), 1.41 (s, 9H); MS: 458 [M⁺H]⁺.

Example 299N-{3-[5-(2-amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-oxazol-4-yl]-2-fluorophenyl}-3-furansulfonamide

Following a procedure analogous to the procedure described in Example52, Step B usingN-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-oxazol-4-yl]-2-fluorophenyl}-3-furansulfonamide(85 mg, 0.178 mmol) and ammonium hydroxide (5 mL), the title compoundwas obtained as an off-white solid (74 mg, 91%). ¹H-NMR (DMSO-d6): δ ppm10.25 (br s, 1H), 8.27 (s, 1H), 8.25 (d, J=5.2 Hz, 1H), 7.83 (t, J=2.0Hz, 1H), 7.44-7.36 (m, 2H), 7.25 (t, J=8.4 Hz, 1H), 6.69 (s, 1H), 6.63(br s, 2H), 6.50 (d, J=5.2 Hz, 1H), 1.41 (s, 9H); MS: 458 [M⁺H]⁺.

Example 300N-{2-fluoro-3-[5-{2-[(2-hydroxyethyl)amino]-4-pyrimidinyl}-2-(tetrahydro-2H-pyran-4-yl)-1,3-thiazol-4-yl]phenyl}-3-furansulfonamide

To the solution ofN-{3-[5-(2-chloro-4-pyrimidinyl)-2-(tetrahydro-2H-pyran-4-yl)-1,3-thiazol-4-yl]-2-fluorophenyl}-3-furansulfonamide(110 mg, 0.211 mmol) in toluene (2 ml) was added ethanol amine (64.5 mg,1.056 mmol) and the reaction mixture heated in MW for 30 min at 140° C.Methanol (1 ml) was added and solution was purified by chromatography(100% EtOAc to 20% MeOH:EtOAc).N-{2-fluoro-3-[5-{2-[(2-hydroxyethyl)amino]-4-pyrimidinyl}-2-(tetrahydro-2H-pyran-4-yl)-1,3-thiazol-4-yl]phenyl}-3-furansulfonamide(53 mg, 43.7%) was isolated as white powder. ¹H NMR (400 MHz, DMSO-d₆)ppm 1.74 (qd, J=12.19, 4.48 Hz, 2H), 2.01 (dd, J=12.66, 2.12 Hz, 2H),3.21-3.34 (m, 4H), 3.42-3.57 (m, 4H), 3.93 (dt, J=9.58, 2.22 Hz, 2H),4.67 (t, J=6.00 Hz, 1H), 6.66 (t, J=1.29 Hz, 1H), 7.17 (t, J=5.75 Hz,1H), 7.24-7.40 (m, 2H), 7.46 (td, J=7.69, 1.99 Hz, 1H), 7.82 (t, J=1.80Hz, 1H), 8.08 (d, J=5.18 Hz, 1H), 8.28 (t, J=1.20 Hz, 1H), 10.31 (s,1H); MS (ESI): 546.1 [M+H]⁺.

Example 301N-{3-[5-(2-{[2-(diethylamino)ethyl]amino}-4-pyrimidinyl)-2-(tetrahydro-2H-pyran-4-yl)-1,3-thiazol-4-yl]-2-fluorophenyl}-3-furansulfonamide

Following a procedure analogous to the procedure described in example300 usingN-{3-[5-(2-chloro-4-pyrimidinyl)-2-(tetrahydro-2H-pyran-4-yl)-1,3-thiazol-4-yl]-2-fluorophenyl}-3-furansulfonamide(110 mg, 0.211 mmol), N,N-diethyl-1,2-ethanediamine (123 mg, 1.056 mmol)in 1,4-dioxane (2 mL), the title compound was obtained as a yellow foam(30 mg, 22.47%). ¹H NMR (400 MHz, DMSO-d₆) ppm 1.01 (t, J=6.44 Hz, 6H),1.65-1.83 (m, 2H), 2.01 (dd, J=12.76, 1.89 Hz, 2H), 2.58-2.73 (m, 6H),3.27-3.41 (m, 5H), 3.42-3.58 (m, 2H), 3.93 (dt, J=9.54, 2.18 Hz, 2H),5.78-6.17 (m, 1H), 6.60 (d, J=1.26 Hz, 1H), 6.97-7.28 (m, 3H), 7.43 (td,J=7.77, 1.64 Hz, 1H), 7.75 (s, 1H), 7.96-8.30 (m, 2H); MS (ESI): 601.2[M+H]⁺.

Example 302N-{2-fluoro-3-[5-(2-{[(2R)-2-hydroxypropyl]amino}-4-pyrimidinyl)-2-(tetrahydro-2H-pyran-4-yl)-1,3-thiazol-4-yl]phenyl}-3-furansulfonamide

Following a procedure analogous to the procedure described in example300 usingN-{3-[5-(2-chloro-4-pyrimidinyl)-2-(tetrahydro-2H-pyran-4-yl)-1,3-thiazol-4-yl]-2-fluorophenyl}-3-furansulfonamide(110 mg, 0.211 mmol), (R)-(−)-1-aminopropanol (79 mg, 1.056 mmol) in1,4-dioxane (2 mL), the title compound was obtained as a yellow foam (48mg, 0.081 mmol, 38.6%). ¹H NMR (400 MHz, DMSO-d₆) ppm 0.93-1.12 (m, 3H),1.75 (qd, J=12.13, 4.29 Hz, 2H), 2.02 (d, J=1.77 Hz, 1H), 3.00-3.24 (m,2H), 3.24-3.33 (m, 1H), 3.40-3.59 (m, 2H), 3.78 (dt, J=10.67, 5.65 Hz,1H), 3.93 (dd, J=11.24, 2.15 Hz, 2H), 4.69 (d, J=1.26 Hz, 1H), 5.79-6.06(m, 1H), 6.66 (d, J=1.26 Hz, 1H), 7.13 (t, J=5.81 Hz, 1H), 7.20-7.40 (m,2H), 7.40-7.53 (m, 1H), 7.81 (t, J=1.77 Hz, 1H), 8.08 (d, J=5.05 Hz,1H), 8.27 (s, 1H), 10.30 (br. s., 1H); MS (ESI): 560.1 [M+H]⁺.

Example 303N-{2-fluoro-3-[5-(2-{[(2S)-2-hydroxypropyl]amino}-4-pyrimidinyl)-2-(tetrahydro-2H-pyran-4-yl)-1,3-thiazol-4-yl]phenyl}-3-furansulfonamide

Following a procedure analogous to the procedure described in example300 usingN-{3-[5-(2-chloro-4-pyrimidinyl)-2-(tetrahydro-2H-pyran-4-yl)-1,3-thiazol-4-yl]-2-fluorophenyl}-3-furansulfonamide(110 mg, 0.211 mmol), (S)-(+)-1-amino-2-propanol (79 mg, 1.056 mmol) in1,4-dioxane (2 mL), the title compound was obtained as a white foam (44mg, 0.075 mmol, 35.4%). ¹H NMR (400 MHz, DMSO-d₆) ppm 1.05 (d, J=6.32Hz, 3H), 1.75 (qd, J=12.13, 4.04 Hz, 2H), 1.99-2.09 (m, 2H), 2.98-3.24(m, 2H), 3.29 (tt, J=11.49, 3.92 Hz, 1H), 3.39-3.53 (m, 2H), 3.78 (dt,J=11.31, 5.84 Hz, 1H), 3.93 (dd, J=11.49, 2.15 Hz, 2H), 4.69 (br s.,1H), 5.94 (d, J=1.26 Hz, 1H), 6.66 (d, J=1.01 Hz, 1H), 7.13 (t, J=5.81Hz, 1H), 7.23-7.39 (m, 2H) 7.46 (t, J=6.95 Hz, 1H), 7.82 (t, J=1.77 Hz,1H), 8.08 (d, J=5.05 Hz, 1H), 8.28 (s, 1H), 10.32 (s, 1H); MS (ESI):560.0 [M+H]⁺.

Example 304N-{2-fluoro-3-[5-{2-[(2-methylpropyl)amino]-4-pyrimidinyl}-2-(tetrahydro-2H-pyran-4-yl)-1,3-thiazol-4-yl]phenyl}-3-furansulfonamide

Following a procedure analogous to the procedure described in example300 usingN-{3-[5-(2-chloro-4-pyrimidinyl)-2-(tetrahydro-2H-pyran-4-yl)-1,3-thiazol-4-yl]-2-fluorophenyl}-3-furansulfonamide(110 mg, 0.211 mmol), isobutylamine (77 mg, 1.056 mmol) in 1,4-dioxane(2 mL), the title compound was obtained as a yellow foam (28 mg, 0.048mmol, 22.59%). ¹H NMR (400 MHz, DMSO-d₆) ppm 0.87 (d, J=6.57 Hz, 7H),1.76 (td, J=12.00, 3.79 Hz, 3H), 1.94-2.06 (m, 2H), 3.25-3.34 (m, 2H),3.41-3.50 (m, 2H), 3.93 (dt, J=9.66, 2.12 Hz, 2H), 5.79-6.04 (m, 1H),6.66 (d, J=1.26 Hz, 1H), 7.20-7.41 (m, 3H), 7.41-7.56 (m, 1H), 7.81 (t,J=1.77 Hz, 1H), 8.08 (d, J=5.30 Hz, 1H), 8.28 (s, 1H), 10.31 (s, 1H); MS(ESI): 558.0 [M+H]⁺.

Example 305N-(2-fluoro-3-{2-(tetrahydro-2H-pyran-4-yl)-5-[2-(tetrahydro-2H-pyran-4-ylamino)-4-pyrimidinyl}-1,3-thiazol-4-yl]phenyl)-3-furansulfonamide

Following a procedure analogous to the procedure described in example300 usingN-{3-[5-(2-chloro-4-pyrimidinyl)-2-(tetrahydro-2H-pyran-4-yl)-1,3-thiazol-4-yl]-2-fluorophenyl}-3-furansulfonamide(110 mg, 0.211 mmol), 4-aminotetrahydropyrane (107 mg, 1.056 mmol) in1,4-dioxane (2 mL), the title compound was obtained as a brown foam (20mg, 0.032 mmol, 15%). ¹H NMR (400 MHz, DMSO-d₆) ppm 1.33-1.63 (m, 2H),1.75 (qd, J=11.96, 4.29 Hz, 4H), 1.99-2.05 (m, 2H), 3.19-3.39 (m, 5H),3.47 (td, J=11.62, 1.77 Hz, 2H), 3.78-3.90 (m, 2H), 3.90-3.98 (m, 2H),6.66 (d, J=1.26 Hz, 1H), 7.23-7.38 (m, 3H), 7.45 (t, J=6.95 Hz, 1H),7.82 (t, J=1.77 Hz, 1H), 8.11 (d, J=4.55 Hz, 1H), 8.28 (s, 1H), 10.32(s, 1H); MS (ESI): 586.0 [M+H]⁺.

Example 306N-{2-fluoro-3-[5-(2-{[2-(1-pyrrolidinyl)ethyl]amino}-4-pyrimidinyl)-2-(tetrahydro-2H-pyran-4-yl)-1,3-thiazol-4-yl]phenyl}-3-furansulfonamide

Following a procedure analogous to the procedure described in example300 usingN-{3-[5-(2-chloro-4-pyrimidinyl)-2-(tetrahydro-2H-pyran-4-yl)-1,3-thiazol-4-yl]-2-fluorophenyl}-3-furansulfonamide(110 mg, 0.211 mmol), [2-(1-pyrrolidinyl)ethyl]amine (121 mg, 1.056mmol) in 1,4-dioxane (2 mL)), the title compound was obtained as a whitefoam (30 mg, 22%). ¹H NMR (400 MHz, DMSO-d₆) ppm 1.58-1.87 (m, 6H), 2.01(dd, J=12.88, 2.02 Hz, 2H), 2.54-2.88 (m, 6H), 3.12-3.43 (m, 3H), 3.47(td, J=11.62, 2.02 Hz, 2H), 3.93 (dt, J=9.47, 2.21 Hz, 2H), 5.77 (s,1H), 5.91-6.31 (m, 1H), 6.56 (d, J=1.26 Hz, 1H), 6.92 (br. s., 1H), 7.07(t, J=7.71 Hz, 1H), 7.18 (br. s., 1H), 7.41 (td, J=8.02, 1.64 Hz, 1H),7.70 (t, J=1.77 Hz, 1H), 8.05 (s, 1H), 8.11 (d, J=5.05 Hz, 1H); MS(ESI): 599.1 [M+H]⁺.

Example 307N-{2-fluoro-3-[5-(2-{[2-(4-morpholinyl)ethyl]amino}-4-pyrimidinyl)-2-(tetrahydro-2H-pyran-4-yl)-1,3-thiazol-4-yl]phenyl}-3-furansulfonamide

Following a procedure analogous to the procedure described in example300 usingN-{3-[5-(2-chloro-4-pyrimidinyl)-2-(tetrahydro-2H-pyran-4-yl)-1,3-thiazol-4-yl]-2-fluorophenyl}-3-furansulfonamide(110 mg, 0.211 mmol), [2-(4-morpholinyl)ethyl]amine (137 mg, 1.056 mmol)in 1,4-dioxane (2 mL), the title compound was obtained as a white foam(35 mg, 25.6%. ¹H NMR (400 MHz, DMSO-d₆) ppm 1.62-1.83 (m, 2H), 2.01(dd, J=12.76, 2.15 Hz, 2H), 2.35-2.47 (m, 7H), 3.23-3.32 (m, 2H), 3.47(td, J=11.56, 1.89 Hz, 2H), 3.57 (t, J=4.42 Hz, 4H), 3.93 (dt, J=9.35,2.27 Hz, 2H), 5.81-6.11 (m, 1H), 6.64 (s, 1H), 7.13 (t, J=5.31 Hz, 1H),7.24 (d, J=5.56 Hz, 2H), 7.44 (dt, J=9.66, 3.76 Hz, 1H), 7.79 (s, 1H),8.09 (d, J=5.30 Hz, 1H), 8.23 (s, 1H), 10.32 (d, J=1.01 Hz, 1H); MS(ESI): 615.1 [M+H]⁺.

Example 308 and Example 3092-[5-(2-Amino-4-pyrimidinyl)-4-(3-{[(2,6-difluorophenyl)sulfonyl]amino}-2-fluorophenyl)-1,3-thiazol-2-yl]-2-methylpropanoicacid and2-[5-(2-Amino-4-pyrimidinyl)-4-(3-{[(2,6-difluorophenyl)sulfonyl]amino}-2-fluorophenyl)-1,3-thiazol-2-yl]-2-methylpropanamideStep A: 3-Hydroxy-2,2-dimethylpropanethioamide

ethyl 2-cyano-2-methylpropanoate (2.5 g, 17.71 mmol) anddiphenylphosphinodithioic acid (8.86 g, 35.4 mmol) in isopropanol (150mL) were heated to reflux overnight, then cooled to ambient temperature.The mixture was transferred in a freezer for 50 minutes then filteredrapidly (white deposit produced during freezer storage was left behind).The filtrate was evaporated, residue dissolved in DCM (250 mL) and thesolution washed sequentially with 100 mL each of water, 1N-NaOH and sat.aq. sodium bicarbonate. After drying (MgSO4), the solution was filteredand filtrate evaporated to give clear liquid which was flashchromatographed on silica gel to afford the title compound as a yellowliquid (0.43 g, 14%). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 9.73 (br s, 1H)8.82 (br s, 1H) 3.96-4.15 (q, J=7.07 Hz, 2H) 1.40 (s, 6H) 1.16 (t,J=7.07 Hz, 3H), MS (ESI) 175.0 [M+H]⁺.

Step B: Ethyl2-[5-(2-chloro-4-pyrimidinyl)-4-(3-{[(2,6-difluorophenyl)sulfonyl]amino}-2-fluorophenyl)-1,3-thiazol-2-yl]-2-methylpropanoate

Following a procedure analogous to the procedure described forIntermediate 9 usingN-{3-[(2-chloro-4-pyrimidinyl)acetyl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide(962 mg, 2.18 mmol) and 3-hydroxy-2,2-dimethylpropanethioamide (394 mg,2.26 mmol), the title compound was obtained as a white foam (940 mg, 72%yield). A portion of the sample was crystallized from ethylacetate-hexanes. ¹H NMR (400 MHz, DMSO-d₆) d ppm 10.93 (s, 1H), 8.58 (d,J=5.31 Hz, 1H), 7.63-7.76 (m, 1H), 7.41-7.52 (m, 2H), 7.29-7.38 (m, 1H),7.24 (t, J=8.97 Hz, 2H), 6.91 (d, J=5.31 Hz, 1H), 4.14 (q, J=7.07 Hz,2H), 1.67 (s, 6H), 1.15 (t, J=7.07 Hz, 3H). MS (ESI): 597.0, 598.5[M+H]⁺.

Step C:2-[5-(2-Amino-4-pyrimidinyl)-4-(3-{[(2,6-difluorophenyl)sulfonyl]amino}-2-fluorophenyl)-1,3-thiazol-2-yl]-2-methylpropanoicacid and2-[5-(2-Amino-4-pyrimidinyl)-4-(3-{[(2,6-difluorophenyl)sulfonyl]amino}-2-fluorophenyl)-1,3-thiazol-2-yl]-2-methylpropanamide

A solution of ethyl2-[5-(2-chloro-4-pyrimidinyl)-4-(3-{[(2,6-difluorophenyl)sulfonyl]amino}-2-fluorophenyl)-1,3-thiazol-2-yl]-2-methylpropanoate(75 mg, 0.126 mmol) and saturated aqueous ammonium hydroxide (16.0 mL)were heated in a microwave reactor to 90° C. for 15 minutes.

The reaction mixture was concentrated, diluted with water, and extractedwith ethyl acetate (6×25 mL) and chloroform (1×25 mL). The combinedorganics were dried (MgSO4), filtered and filtrate evaporated; theresidue was set aside. The pH of the aqueous phase was adjusted to ˜13with 1N-NaOH (total vol. ˜8 mL) and the solution passed through “DiaionHP20SS” resin eluting first with water, then acetone-water mixtures.Product-containing fraction (ILCMS monitoring) was, concentrated,adjusted to pH 12 and lyophilized to give2-[5-(2-amino-4-pyrimidinyl)-4-(3-{[(2,6-difluorophenyl)sulfonyl]amino}-2-fluorophenyl)-1,3-thiazol-2-yl]-2-methylpropanoicacid, disodium salt (4.9 mg). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.95 (d,J=5.05 Hz, 1H) 7.30-7.40 (m, 1H) 7.21-7.28 (m, 1H) 6.92-7.03 (m, 2H)6.80 (t, J=7.83 Hz, 1H) 6.58 (s, 2H) 6.46-6.52 (m, 1H) 6.09 (d, J=4.55Hz, 1H) 1.44 (s, 6H). MS (ESI): 550.0 [M+H]⁺.

Organic residue from above work-up was chromatographed on silica geleluting with an ethyl acetate/hexanes gradient. The second-elutingfraction was2-[5-(2-amino-4-pyrimidinyl)-4-(3-{[(2,6-difluorophenyl)sulfonyl]amino}-2-fluorophenyl)-1,3-thiazol-2-yl]-2-methylpropanamide.Fractions containing this material were combined and evaporated to whitefoam (35 mg) which was crystallized from ethyl acetate-hexanes. ¹H NMR(400 MHz, chloroform-d) δ ppm 8.03 (d, J=5.31 Hz, 1H), 7.72-7.80 (m,1H), 7.49-7.59 (m, 1H), 7.27-7.35 (m, 2H), 7.15 (br s, 1H), 7.02 (t,J=8.46 Hz, 2H), 6.16 (d, J=5.05 Hz, 1H), 5.35 (br. s., 1H), 5.07 (br. s,2H), 1.77 (s, 6H). MS (ESI): 549.0 [M+H]⁺.

Example 310N-{3-[2-(1-amino-1-methylethyl)-5-(2-methyl-4-pyrimidinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide

Step A: 1,1-dimethylethyl (2-amino-1,1-dimethyl-2-thioxoethyl)carbamate

N²-{[(1,1-dimethylethyl)oxy]carbonyl}-2-methylalaninamide (3.87 g, 19.13mmol), Lawesson's reagent (7.74 g, 19.13 mmol) and tetrahydrofuran (THF)(100 mL) was heated to 50° C. for 3 hours. The reaction wasconcentrated, added 150 cc of EtOAc and washed with sat'd NaHCO₃ (3×100cc), water and brine. The EtOAc layer was concentrated and the residuewas purified via chromatography on silica gel eluted Hex to 1:1Hex/EtOAc to obtain the title compound (2.04 g, 48% yield).

Step B: 2-propen-1-yl(3-{5-(2-chloro-4-pyrimidinyl)-2-[1-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-1-methylethyl]-1,3-thiazol-4-yl}-2-fluorophenyl)carbamate

N-Bromosuccinimide (0.763 g, 4.29 mmol) was added to a solution of2-propen-1-yl{3-[(2-chloro-4-pyrimidinyl)acetyl]-2-fluorophenyl}carbamate (1.5 g,4.29 mmol) in dichloromethane (DCM) (50 mL). After 1 h of stirring,1,1-dimethylethyl (2-amino-1,1-dimethyl-2-thioxoethyl)carbamate (0.936g, 4.29 mmol) was added to the reaction mixture and heated to 80° C. for2 h. The reaction mixture was diluted with 150 cc of EtOAc and washedwith water (5×100 cc). The EtOAc layer was dried over MgSO₄ and filteredand concentrated in vacuo. The residue was purified via chromatographyon silica gel using Hex to 25% EtOAc in Hex to obtain the title compound(1.28 g, 54% yield). MS (ESI): 548.3 [M+H]+

Step C: 1,1-dimethylethyl{1-[4-(3-amino-2-fluorophenyl)-5-(2-chloro-4-pyrimidinyl)-1,3-thiazol-2-yl]-1-methylethyl}carbamate

To a solution of 2-propen-1-yl(3-{5-(2-chloro-4-pyrimidinyl)-2-[1-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-1-methylethyl]-1,3-thiazol-4-yl}-2-fluorophenyl)carbamate(1.28 g, 2.336 mmol). tri-n-butyltin hydride (0.624 mL, 2.336 mmol) indichloromethane (DCM) (50 mL) was addedtetrakis(triphenyl-phosphine)palladium(0) (0.135 g, 0.117 mmol) followedby water (0.2 mL). After 30 min, the reaction was concentrated. Theresidue was purified via chromatography on silica gel to obtain thetitle compound (0.81 g 74% yield). MS (ESI): 464.1 [M+H]+

Step D: 1,1-dimethylethyl{1-[5-(2-chloro-4-pyrimidinyl)-4-(3-{[(2,6-difluorophenyl)sulfonyl]amino}-2-fluorophenyl)-1,3-thiazol-2-yl]-1-methylethyl}carbamate

To a solution of 1,1-dimethylethyl{1-[4-(3-amino-2-fluorophenyl)-5-(2-chloro-4-pyrimidinyl)-1,3-thiazol-2-yl]-1-methylethyl}carbamate(400 mg, 0.862 mmol) in pyridine (50 mL) was added dropwise2,6-difluorobenzenesulfonyl chloride (238 mg, 1.121 mmol). After 4 h,2,6-difluorobenzenesulfonyl chloride (0.20 g) was added to the reactionmixture and stirred at rt overnight. The reaction mixture wasconcentrated. The residue was purified via chromatography on silica gelto obtain the title compound (330 mg 59% yield). MS (ESI): 639.9 [M+H]+

Step E:N-{3-[2-(1-amino-1-methylethyl)-5-(2-methyl-4-pyrimidinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide

N-{3-[2-(1-amino-1-methylethyl)-5-(2-methyl-4-pyrimidinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamidewas dissolved in 1,4-dioxane (40 mL) and was degassed for 10 minutes. Tothis solution was added1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloridedichloromethane complex (0.017 g, 0.020 mmol) followed by dimethylzinc(0.406 mL, 0.812 mmol) and was heated to 80° C. for 3 hours. Thereaction mixture was quenched by addition of 1 ml of MeOH. The reactionwas diluted with 50 ml of DCM and 50 ml of water, filtered and separatedphases. The water was extracted with 50 cc of DCM (2×). The combinedorganic phases were washed with water. The DCM layers were dried overMgSO₄, filtered and concentrated in vacuo. The residue waschromatographed on silica gel (Hex:EtOAc). The residue was dissolved in3 ml of DCM and added 3 ml of TFA and stirred stir at rt for 30 minutes.The reaction mixture was concentrated in vacuo. The residue wasdissolved in 10 ml of MeOH. Conc. HCl (2 cc) was added to the reactionmixture and concentrated in vacuo. The residue was dissolved in MeOH,added HCl and concentrated to give conc. HCl salt of product. Free basewas obtained by addition of sat'd NaHCO₃ (22 cc) to the HCl salt andextracted with DCM (3×30 cc). DCM extracts were washed with brine anddried over MgSO₄, filtered and concentrated in vacuo to obtain the titlecompound (43 mg 20% yield). MS (ESI): 520.1 [M+H]+

Example 311N-{3-[2-(1-amino-1-methylethyl)-5-(2-methyl-4-pyrimidinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-3-furansulfonamide

Step A:1,1-dimethylethyl[1-(5-(2-chloro-4-pyrimidinyl)-4-{2-fluoro-3-[(3-furanylsulfonyl)amino]phenyl}-1,3-thiazol-2-yl)-1-methylethyl]carbamate

To a solution of 1,1-dimethylethyl{1-[4-(3-amino-2-fluorophenyl)-5-(2-chloro-4-pyrimidinyl)-1,3-thiazol-2-yl]-1-methylethyl}carbamate(400 mg, 0.862 mmol) in pyridine (50 mL) was added 3-furansulfonylchloride (144 mg, 0.862 mmol) (in 5 cc DCM). After 4 h, 3-furansulfonylchloride (0.20 g) was to the reaction mixture and stirred at rtovernight. The reaction mixture was concentrated in vacuo. The residuewas purified via Biotage (3:1-Hex/EtOAc; 25M silica gel column) toobtain the title compound (460 mg 90% yield). MS (ESI): 594.2 [M+H]+

N-{3-[2-(1-amino-1-methylethyl)-5-(2-methyl-4-pyrimidinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-3-furansulfonamide

1,1-dimethylethyl[1-(5-(2-chloro-4-pyrimidinyl)-4-{2-fluoro-3-[(3-furanylsulfonyl)amino]phenyl}-1,3-thiazol-2-yl)-1-methylethyl]carbamate(310 mg, 0.522 mmol) was dissolved in 1,4-dioxane (40 mL) and wasdegassed for 10 minutes. To this solution was added1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloridedichloromethane complex (21.31 mg, 0.026 mmol) followed by dimethylzinc(0.522 mL, 1.044 mmol) and heated to 80° C. for 3 hours. The reactionmixture was quenched by addition of 1 ml of MeOH. The reaction mixturewas diluted with 50 ml of DCM and 50 ml of water, filtered and separatedphases. The aqueous layer was extracted 50 cc of DCM (2×). The combinedorganic phases were washed with water and dried over MgSO₄, filtered,and concentrated in vacuo. The residue was chromatographed on silica gel(Hex:EtOAc). The residue was dissolved in 3 ml of DCM and added 3 ml ofTFA and stirred at rt for 30 minutes. The reaction was concentrated invacuo. The residue was dissolved in 10 ml of MeOH and added 3 cc ofconc. HCl and concentrated in vacuo. The residue was dissolved in MeOH,added HCl, and concentrated to give HCl salt of product. Free base wasobtained by adding 20 cc of sat'd NaHCO₃ to the HCl salt and extractedwith DCM (3×30 cc). DCM extracts was washed with brine and dried overMgSO₄, filtered and concentrated in vacuo to obtain the title compound(68 mg 24% yield). MS (ESI): 574.1 [M+H]+

Example 312N-{3-[2-(1-amino-1-methylethyl)-5-(2-amino-4-pyrimidinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-3-furansulfonamide

1,1-dimethylethyl[1-(5-(2-chloro-4-pyrimidinyl)-4-{2-fluoro-3-[(3-furanylsulfonyl)amino]phenyl}-1,3-thiazol-2-yl)-1-methylethyl]carbamate(100 mg, 0.168 mmol) and ammonium hydroxide (2 ml, 51.4 mmol) wasmicrowaved at 90° C. for 3 hours. The reaction was cooled in ice waterbath before opening microwave vial to relieve pressure. The reaction wasconcentrated to dryness in vacuo. The residue was diluted with 50 ml ofDCM and 50 ml of water and adjusted pH to about 4 to 5 by addition of 1NHCl and separated phases. The water was extracted with 50 cc of DCM(3×50 cc). The combined DCM phases were washed with water and dried overMgSO₄, filtered, and concentrated in vacuo. The residue was dissolved in3 ml of DCM and added 3 ml of TFA and stirred at rt for 30 minutes. Thereaction mixture was concentrated in vacuo. The residue was dissolved in10 ml of MeOH and added 3 ml of conc. HCl and concentrated in vacuo. Theresidue again was dissolved in MeOH, added conc. HCl and concentrated invacuo to yield the HCl salt of the product. Free base was obtained byaddition of 20 cc of sat'd NaHCO₃ to the HCl salt and extracted with DCM(3×30 cc). DCM extracts was washed with brine and dried over MgSO₄,filtered, and concentrated in vacuo to obtain the title compound (48 mg60% yield). MS (ESI): 474.8 [M+H]+

Example 313N-{3-[2-(1-amino-1-methylethyl)-5-(2-amino-4-pyrimidinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide

Following a procedure analogous to the procedure described in Example312 using 1,1-dimethylethyl{1-[5-(2-chloro-4-pyrimidinyl)-4-(3-{[(2,6-difluorophenyl)sulfonyl]amino}-2-fluorophenyl)-1,3-thiazol-2-yl]-1-methylethyl}carbamate(100 mg, 0.156 mmol) and ammonium hydroxide (2 mL, 51.4 mmol) at 90° C.for 3 hours, the title compound was obtained as a solid (37 mg 45%yield). MS (ESI): 521.2 [M+H]+

Example 314N-{2-fluoro-3-[5-(2-methyl-4-pyrimidinyl)-2-(tetrahydro-2H-pyran-4-yl)-1,3-thiazol-4-yl]phenyl}-3-furansulfonamide

Following a procedure analogous to the procedure described in Example 25usingN-{3-[5-(2-chloro-4-pyrimidinyl)-2-(tetrahydro-2H-pyran-4-yl)-1,3-thiazol-4-yl]-2-fluorophenyl}-3-furansulfonamide(200 mg, 0.384 mmol)mmol) and dimethylzinc (384 μl, 0.768 mmol) at 80°C. for 3 hours, the title compound was obtained as a solid (60 mg, 31%yield). MS (ESI): 500.8 [M+H]+

Example 3152,6-difluoro-N-{2-fluoro-3-[5-(2-methyl-4-pyrimidinyl)-2-(tetrahydro-2H-pyran-4-yl)-1,3-thiazol-4-yl]phenyl}benzenesulfonamide

Following a procedure analogous to the procedure described in Example 25usingN-{3-[5-(2-chloro-4-pyrimidinyl)-2-(tetrahydro-2H-pyran-4-yl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide(300 mg, 0.529 mmol) and dimethylzinc (529 μl, 1.058 mmol) at 80° C. for3 hours, the title compound was obtained as a solid (60 mg, 31% yield).MS (ESI): 547.1 [M+H]+

Example 3162,6-difluoro-N-{2-fluoro-3-[2-(2-hydroxy-1,1-dimethylethyl)-5-(2-methyl-4-pyrimidinyl)-1,3-thiazol-4-yl]phenyl}benzenesulfonamide

Following a procedure analogous to the procedure described in Example 25usingN-{3-[5-(2-chloro-4-pyrimidinyl)-2-(2-hydroxy-1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide(200 mg, 0.360 mmol) and dimethylzinc (0.360 mL, 0.721 mmol) at 80° C.for 3 hours, the title compound was obtained as a solid (8 mg, 4%yield). MS (ESI): 534.9 [M+H]+

Example 3172,6-difluoro-N-{2-fluoro-3-[2-(4-methyl-4-piperidinyl)-5-(2-methyl-4-pyrimidinyl)-1,3-thiazol-4-yl]phenyl}benzenesulfonamide

Step A: 1,1-dimethylethyl4-[5-(2-chloro-4-pyrimidinyl)-4-(2-fluoro-3-{[(2-propen-1-yloxy)carbonyl]amino}phenyl)-1,3-thiazol-2-yl]-4-methyl-1-piperidinecarboxylate

To a solution of 2-propen-1-yl{3-[(2-chloro-4-pyrimidinyl)acetyl]-2-fluorophenyl}carbamate (0.738 g,2.110 mmol) in N,N-dimethylacetamide (8 mL) was added NBS (0.376 g,2.110 mmol), and the reaction mixture was stirred for 1.5 h.1,1-Dimethylethyl4-(aminocarbonothioyl)-4-methyl-1-piperidinecarboxylate (0.545 g, 2.110mmol) was added and the mixture was heated to 80° C. for 30 min. Thereaction mixture was cooled, quenched with water (20 mL), and extractedwith EtOAc (3×). The extract was dried over Na₂SO₄, filtered andconcentrated. The residue was purified using column chromatography(hexane/EtOAc, 0 to 100%) to obtain the title compound (670 mg). MS(ESI): 588.2 [M+1]⁺.

Step B: 1,1-dimethylethyl4-[4-(3-amino-2-fluorophenyl)-5-(2-chloro-4-pyrimidinyl)-1,3-thiazol-2-yl]-4-methyl-1-piperidinecarboxylate

To a solution of 1,1-dimethylethyl4-[5-(2-chloro-4-pyrimidinyl)-4-(2-fluoro-3-{[(2-propen-1-yloxy)carbonyl]amino}phenyl)-1,3-thiazol-2-yl]-4-methyl-1-piperidinecarboxylate(670 mg, 1.139 mmol) in dichloromethane (8 mL) were addedtributylstannane (332 mg, 1.139 mmol), tetrakis (65.8 mg, 0.057 mmol)and water (66 μl, 3.66 mmol). The reaction mixture was stirred for 1 h.The reaction mixture was concentrated and residue was purified usingcolumn chromatography (hexane/EtOAc, 0 to 100%) to obtain the titlecompound (482 mg). MS (ESI): 504.2 [M+1]⁺.

Step C: 1,1-dimethylethyl4-[5-(2-chloro-4-pyrimidinyl)-4-(3-{[(2,6-difluorophenyl)sulfonyl]amino}-2-fluorophenyl)-1,3-thiazol-2-yl]-4-methyl-1-piperidinecarboxylate

To a solution of 1,1-dimethylethyl4-[4-(3-amino-2-fluorophenyl)-5-(2-chloro-4-pyrimidinyl)-1,3-thiazol-2-yl]-4-methyl-1-piperidinecarboxylate(200 mg, 0.397 mmol) in pyridine (2 mL) was added2,6-difluorobenzenesulfonyl chloride (130 mg, 0.612 mmol) and thereaction mixture was stirred for 5 h. The reaction mixture was quenchedwith water (5 mL) and extracted with EtOAc (3×). The extract was dried,filtered and concentrated. The residue was purified using columnchromatography (40 to 100% EtOAc/hexane) to obtain the title compound(220 mg). MS (ESI): 680.4 [M+1]⁺.

Step D: 1,1-dimethylethyl4-[4-(3-{[(2,6-difluorophenyl)sulfonyl]amino}-2-fluorophenyl)-5-(2-methyl-4-pyrimidinyl)-1,3-thiazol-2-yl]-4-methyl-1-piperidinecarboxylate

1,1-dimethylethyl4-[5-(2-chloro-4-pyrimidinyl)-4-(3-{[(2,6-difluorophenyl)sulfonyl]amino}-2-fluorophenyl)-1,3-thiazol-2-yl]-4-methyl-1-piperidinecarboxylate(150 mg, 0.221 mmol) was dissolved into 1,4-dioxane (3 mL) and thesolution was degassed for 10 min. PdCl₂(dppf)-CH₂Cl₂ adduct (9.00 mg,0.011 mmol) and dimethylzinc (0.221 mL, 0.441 mmol) were then added. Thereaction mixture was stirred at 80° C. for 1 h. The reaction mixture wasquenched with methanol (3 mL) and water (10 mL) and extracted with EtOAc(3×). The extract was dried over Na₂SO₄, filtered, and concentrated. Theresidue was purified using column chromatography (40% to 100%EtOAc/hexane) to obtain the title compound (75 mg). MS (ESI): 660.5[M+1]⁺.

Step E:2,6-difluoro-N-{2-fluoro-3-[2-(4-methyl-4-piperidinyl)-5-(2-methyl-4-pyrimidinyl)-1,3-thiazol-4-yl]phenyl}benzenesulfonamide

To a solution of 1,1-dimethylethyl4-[4-(3-{[(2,6-difluorophenyl)sulfonyl]amino}-2-fluorophenyl)-5-(2-methyl-4-pyrimidinyl)-1,3-thiazol-2-yl]-4-methyl-1-piperidinecarboxylate(72 mg, 0.109 mmol) in dichloromethane (2 mL) was added TFA (0.5 mL,6.49 mmol), and the reaction mixture was stirred for 1 h. The reactionwas concentrated and the residue was purified using RP-HPLC. The TFAsalt was neutralized to obtain the title compound (38 mg). MS (ESI):560.0 [M+1]⁺.

Example 318N-{3-[5-(2-amino-4-pyrimidinyl)-2-(4-piperidinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide

Step A: 1,1-dimethylethyl4-[5-(2-amino-4-pyrimidinyl)-4-(3-{[(2,6-difluorophenyl)sulfonyl]amino}-2-fluorophenyl)-1,3-thiazol-2-yl]-4-methyl-1-piperidinecarboxylate

A suspension of 1,1-dimethylethyl4-[5-(2-chloro-4-pyrimidinyl)-4-(3-{[(2,6-difluorophenyl)sulfonyl]amino}-2-fluorophenyl)-1,3-thiazol-2-yl]-4-methyl-1-piperidinecarboxylate(39 mg, 0.057 mmol) in ammonium hydroxide solution (28%, 2 mL, 51.4mmol) sealed in a 5-mL microwave tube was heated at 90° C. for 3 h underthe microwave conditions. The mixture was concentrated and dried underhigh vacuum to obtain the title compound (40 mg). MS (ESI): 661.4[M+1]⁺.

Step B:N-{3-[5-(2-amino-4-pyrimidinyl)-2-(4-piperidinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide

To a solution of 1,1-dimethylethyl4-[5-(2-amino-4-pyrimidinyl)-4-(3-{[(2,6-difluorophenyl)sulfonyl]amino}-2-fluorophenyl)-1,3-thiazol-2-yl]-1-piperidinecarboxylate(94 mg, 0.145 mmol) in dichloromethane (2 mL) was added TFA (0.5 mL,6.49 mmol), and the reaction mixture was stirred for 1 h. the reactionmixture was concentrated and the residue was purified using RP-HPLC. TheTFA salt was neutralized to the title compound (56 mg). MS (ESI): 547.1[M+1]⁺.

Example 319N-{3-[5-(2-amino-4-pyrimidinyl)-2-(4-methyl-4-piperidinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-3-furansulfonamide

Step A: 1,1-dimethylethyl4-(5-(2-chloro-4-pyrimidinyl)-4-{2-fluoro-3-[(3-furanylsulfonyl)amino]phenyl}-1,3-thiazol-2-yl)-4-methyl-1-piperidinecarboxylate

To a solution of 1,1-dimethylethyl4-[4-(3-amino-2-fluorophenyl)-5-(2-chloro-4-pyrimidinyl)-1,3-thiazol-2-yl]-4-methyl-1-piperidinecarboxylate(280 mg, 0.556 mmol) in pyridine (3 mL) was added 3-furansulfonylchloride (139 mg, 0.833 mmol), and the reaction mixture was stirred for3 h. The reaction mixture was quenched with water (5 mL) and extractedwith EtOAc (3×). The extract was dried, filtered and concentrated. Theresidue was purified using column chromatography (40 to 100%EtOAc/hexane) to the title compound (310 mg). MS (ESI): 634.1 [M+1]⁺.

Step B: 1,1-dimethylethyl4-(5-(2-amino-4-pyrimidinyl)-4-{2-fluoro-3-[(3-furanylsulfonyl)amino]phenyl}-1,3-thiazol-2-yl)-4-methyl-1-piperidinecarboxylate

A suspension of 1,1-dimethylethyl4-(5-(2-chloro-4-pyrimidinyl)-4-{2-fluoro-3-[(3-furanylsulfonyl)amino]phenyl}-1,3-thiazol-2-yl)-4-methyl-1-piperidinecarboxylate(65 mg, 0.103 mmol) in ammonium hydroxide solution (28%, 2 mL, 51.4mmol) sealed in a 5-mL microwave tube was heated at 90° C. for 3 h underthe microwave conditions. The mixture was concentrated and dried underhigh vacuum to the title compound (64 mg). MS (ESI): 558.6 [M+1−56]⁺.

Step C:N-{3-[5-(2-amino-4-pyrimidinyl)-2-(4-methyl-4-piperidinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-3-furansulfonamide

To a solution of 1,1-dimethylethyl4-(5-(2-amino-4-pyrimidinyl)-4-{2-fluoro-3-[(3-furanylsulfonyl)amino]phenyl}-1,3-thiazol-2-yl)-4-methyl-1-piperidinecarboxylate(64 mg, 0.104 mmol) in dichloromethane (DCM) (2 mL) was added TFA (500μl, 6.49 mmol), and the reaction mixture was stirred for 1 h. Thereaction mixture was concentrated and the residue was purified usingRP-HPLC. The TFA salt was neutralized to the title compound (37 mg). MS(ESI): 515.2 [M+1]⁺.

Example 320N-{2-fluoro-3-[2-(4-methyl-4-piperidinyl)-5-(2-methyl-4-pyrimidinyl)-1,3-thiazol-4-yl]phenyl}-3-furansulfonamide

Step A: 1,1-dimethylethyl4-[4-{2-fluoro-3-[(3-furanylsulfonyl)amino]phenyl}-5-(2-methyl-4-pyrimidinyl)-1,3-thiazol-2-yl]-4-methyl-1-piperidinecarboxylate

1,1-dimethylethyl4-(5-(2-chloro-4-pyrimidinyl)-4-{2-fluoro-3-[(3-furanylsulfonyl)amino]phenyl}-1,3-thiazol-2-yl)-4-methyl-1-piperidinecarboxylate(130 mg, 0.205 mmol) was dissolved into 1,4-dioxane (3 mL) and thesolution was degassed for 10 min. PdCl₂(dppf)-CH₂Cl₂ adduct (8.37 mg,10.25 μmol) and dimethylzinc (0.205 mL, 0.410 mmol) were added thereaction mixture. The reaction mixture was stirred at 80° C. for 1 h.The reaction was quenched with methanol (3 mL) and water (10 mL) andextracted with EtOAc (3×). The extract was dried over Na₂SO₄, filtered,and concentrated. The residue was purified using column chromatography(40% to 100% EtOAc/hexane) to the title compound (100 mg). MS (ESI):557.7 [M+1]⁺.

Step B:N-{2-fluoro-3-[2-(4-methyl-4-piperidinyl)-5-(2-methyl-4-pyrimidinyl)-1,3-thiazol-4-yl]phenyl}-3-furansulfonamide

To a solution of 1,1-dimethylethyl4-[4-{2-fluoro-3-[(3-furanylsulfonyl)amino]phenyl}-5-(2-methyl-4-pyrimidinyl)-1,3-thiazol-2-yl]-4-methyl-1-piperidinecarboxylate(98 mg, 0.160 mmol) in dichloromethane (DCM) (2 mL) was added TFA (0.5mL, 6.49 mmol), and the reaction mixture was stirred for 1 h. Thereaction mixture was concentrated and the residue was purified usingRP-HPLC. The TFA salt was neutralized to the title compound (26 mg). MS(ESI): 514.2 [M+1]⁺.

Example 3212,6-difluoro-N-{2-fluoro-3-[5-(2-methyl-4-pyrimidinyl)-2-(4-piperidinyl)-1,3-thiazol-4-yl]phenyl}benzenesulfonamide

Step A: 1,1-dimethylethyl4-[5-(2-chloro-4-pyrimidinyl)-4-(2-fluoro-3-{[(2-propen-1-yloxy)carbonyl]amino}phenyl)-1,3-thiazol-2-yl]-1-piperidinecarboxylate

To a solution of 2-propen-1-yl{3-[(2-chloro-4-pyrimidinyl)acetyl]-2-fluorophenyl}-carbamate (1.43 g,4.09 mmol) in N,N-dimethylacetamide (DMA) (15 mL) was added NBS (0.728g, 4.09 mmol), and the reaction mixture was stirred for 1 h.1,1-Dimethylethyl 4-(aminocarbonothioyl)-1-piperidinecarboxylate (0.999g, 4.09 mmol) was added and the reaction mixture was heated to 80° C.for 25 min. The mixture was cooled, quenched with water (30 mL) andextract with EtOAc (3×). The extract was dried over Na2SO4, filtered andconcentrated. The residue was purified using column chromatography(hexane/EtOAc, 0 to 100%) to give 1.34 g of the title compound. MS(ESI): 574.2 [M+1]⁺.

Step B: 1,1-dimethylethyl4-[4-(3-amino-2-fluorophenyl)-5-(2-chloro-4-pyrimidinyl)-1,3-thiazol-2-yl]-1-piperidinecarboxylate

1,1-dimethylethyl4-[5-(2-chloro-4-pyrimidinyl)-4-(2-fluoro-3-{[(2-propen-1-yloxy)carbonyl]amino}phenyl)-1,3-thiazol-2-yl]-1-piperidinecarboxylate(855 mg, 1.489 mmol) was dissolved into dichloromethane (DCM) (8 mL). Tothis solution were added tributylstannane (433 mg, 1.489 mmol), tetrakis(86 mg, 0.074 mmol) and water (0.083 mL, 4.62 mmol), and the reactionmixture was stirred for 1 h and concentrated. The residue was purifiedusing column chromatography (0 to 100% EtOAc/hexane) to give 690 mg ofthe title compound. MS (ESI): 490.1 [M+1]⁺.

Step C: 1,1-dimethylethyl4-[5-(2-chloro-4-pyrimidinyl)-4-(3-{[(2,6-difluorophenyl)sulfonyl]amino}-2-fluorophenyl)-1,3-thiazol-2-yl]-1-piperidinecarboxylate

To a solution of 1,1-dimethylethyl4-[4-(3-amino-2-fluorophenyl)-5-(2-chloro-4-pyrimidinyl)-1,3-thiazol-2-yl]-1-piperidinecarboxylate(300 mg, 0.612 mmol) in pyridine (3 mL) was added2,6-difluorobenzenesulfonyl chloride (130 mg, 0.612 mmol), and thereaction mixture was stirred for 3 h. The reaction mixture was quenchedwith water (5 mL) and extracted with EtOAc (3×). The extracts weredried, filtered and concentrated. The residue was purified using columnchromatography (40 to 100% EtOAc/hexane) to give 324 mg of the titlecompound. MS (ESI): 610.1 [M+1−56]⁺.

Step D: 1,1-dimethylethyl4-[4-(3-{[(2,6-difluorophenyl)sulfonyl]amino}-2-fluorophenyl)-5-(2-methyl-4-pyrimidinyl)-1,3-thiazol-2-yl]-1-piperidinecarboxylate

1,1-dimethylethyl4-[5-(2-chloro-4-pyrimidinyl)-4-(3-{[(2,6-difluorophenyl)sulfonyl]amino}-2-fluorophenyl)-1,3-thiazol-2-yl]-1-piperidinecarboxylate(167 mg, 0.251 mmol) was dissolved into 1,4-dioxane (3 mL) and thesolution was degassed for 10 min. PdCl₂(dppf)-CH₂Cl₂ adduct (10.24 mg,0.013 mmol) and dimethylzinc (0.251 mL, 0.501 mmol) were added to thereaction mixture. The reaction mixture was stirred at 80° C. for 1 h.The reaction was quenched with methanol (3 mL) and water (10 mL) andextracted with EtOAc (3×). The extract was dried over Na₂SO₄, filtered,and concentrated. The residue was purified using column chromatography(40% to 100% EtOAc/hexane) to give the title compound (120 mg). MS(ESI): 646.3 [M+1]⁺.

Step D:2,6-difluoro-N-{2-fluoro-3-[5-(2-methyl-4-pyrimidinyl)-2-(4-piperidinyl)-1,3-thiazol-4-yl]phenyl}benzenesulfonamide

To a solution of 1,1-dimethylethyl4-[4-(3-{[(2,6-difluorophenyl)sulfonyl]amino}-2-fluorophenyl)-5-(2-methyl-4-pyrimidinyl)-1,3-thiazol-2-yl]-1-piperidinecarboxylate(60 mg, 0.093 mmol) in dichloromethane (DCM) (2 mL) was added TFA (0.5μL, 6.49 μmol), and the reaction mixture was stirred for 1 h. Thereaction mixture was concentrated and the residue was purified usingRP-HPLC. The TFA salt was neutralized to give 32 mg of title compound.MS (ESI): 546.1 [M+1]⁺.

Example 322N-{3-[5-(2-amino-4-pyrimidinyl)-2-(4-piperidinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide

Step A: 1,1-dimethylethyl4-[5-(2-amino-4-pyrimidinyl)-4-(3-{[(2,6-difluorophenyl)sulfonyl]amino}-2-fluorophenyl)-1,3-thiazol-2-yl]-1-piperidinecarboxylate

A suspension of 1,1-dimethylethyl4-[5-(2-chloro-4-pyrimidinyl)-4-(3-{[(2,6-difluorophenyl)sulfonyl]amino}-2-fluorophenyl)-1,3-thiazol-2-yl]-1-piperidinecarboxylate(110 mg, 0.165 mmol) in ammonium hydroxide solution (28%, 2 mL, 51.4mmol) sealed in a 5-mL microwave tube was heated at 90° C. for 3 h underthe microwave conditions. The mixture was concentrated and dried underhigh vacuum to give 98 mg of the title compound. MS (ESI): 647.3 [M+1]⁺.

Step B:N-{3-[5-(2-amino-4-pyrimidinyl)-2-(4-piperidinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide

To a solution of 1,1-dimethylethyl4-[5-(2-amino-4-pyrimidinyl)-4-(3-{[(2,6-difluorophenyl)sulfonyl]amino}-2-fluorophenyl)-1,3-thiazol-2-yl]-1-piperidinecarboxylate(94 mg, 0.145 mmol) in dichloromethane (2 mL) was added TFA (0.5 mL,6.49 mmol), and the reaction mixture was stirred for 1 h. The reactionmixture was concentrated and the residue was purified using RP-HPLC. TheTFA salt was neutralized to give 52 mg of the title compound. MS (ESI):547.1 [M+1]⁺.

Example 323N-{2-fluoro-3-[5-(2-methyl-4-pyrimidinyl)-2-(4-piperidinyl)-1,3-thiazol-4-yl]phenyl}-3-furansulfonamide

Step A: 1,1-dimethylethyl4-(5-(2-chloro-4-pyrimidinyl)-4-{2-fluoro-3-[(3-furanylsulfonyl)amino]phenyl}-1,3-thiazol-2-yl)-1-piperidinecarboxylate

To a solution of 1,1-dimethylethyl4-[4-(3-amino-2-fluorophenyl)-5-(2-chloro-4-pyrimidinyl)-1,3-thiazol-2-yl]-1-piperidinecarboxylate(300 mg, 0.612 mmol) in pyridine (3 mL) was added 3-furansulfonylchloride (153 mg, 0.918 mmol, and the reaction mixture was stirred for 3h. The reaction mixture was quenched with water (5 mL) and extractedwith EtOAc (3×). The extract was dried, filtered and concentrated. Theresidue was purified using column chromatography (40 to 100%EtOAc/hexane) to give 310 mg of the title compound. MS (ESI): 620.2,622.2 [M+1]⁺.

Step B 1,1-dimethylethyl4-[4-{2-fluoro-3-[(3-furanylsulfonyl)amino]phenyl}-5-(2-methyl-4-pyrimidinyl)-1,3-thiazol-2-yl]-1-piperidinecarboxylate

1,1-dimethylethyl4-(5-(2-chloro-4-pyrimidinyl)-4-{2-fluoro-3-[(3-furanylsulfonyl)-amino]phenyl}-1,3-thiazol-2-yl)-1-piperidinecarboxylate(150 mg, 0.242 mmol) was dissolved into 1,4-dioxane (3 mL) and thesolution was degassed for 10 min. PdCl₂(dppf)-CH₂Cl₂ adduct (13.83 mg,0.017 mmol) and dimethylzinc (0.242 mL, 0.484 mmol) were added to thereaction mixture. The reaction mixture was stirred at 80° C. for 1 h.The reaction was quenched with methanol (3 mL) and water (10 mL) andextracted with EtOAc (3×). The extract was dried over Na₂SO₄, filtered,and concentrated. The residue was purified using column chromatography(40% to 100% EtOAc/hexane) to give the title compound (118 mg). MS(ESI): 600.3 [M+1]⁺.

Step C:N-{2-fluoro-3-[5-(2-methyl-4-pyrimidinyl)-2-(4-piperidinyl)-1,3-thiazol-4-yl]phenyl}-3-furansulfonamide

To a solution of 1,1-dimethylethyl4-[4-{2-fluoro-3-[(3-furanylsulfonyl)amino]phenyl}-5-(2-methyl-4-pyrimidinyl)-1,3-thiazol-2-yl]-piperidinecarboxylate(115 mg, 0.192 mmol) in dichloromethane (2 mL) was added TFA (0.015 mL,0.192 mmol), and the reaction mixture was stirred for 1 h. The reactionmixture was concentrated and the residue was purified using RP-HPLC. TheTFA salt was neutralized to give 62 mg of the title compound. MS (ESI):500.3 [M+1]⁺.

Example 324N-{3-[5-(2-amino-4-pyrimidinyl)-2-(4-piperidinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-3-furansulfonamide

Step A: 1,1-dimethylethyl4-(5-(2-amino-4-pyrimidinyl)-4-{2-fluoro-3-[(3-furanylsulfonyl)amino]phenyl}-1,3-thiazol-2-yl)-1-piperidinecarboxylate

A suspension of 1,1-dimethylethyl4-(5-(2-chloro-4-pyrimidinyl)-4-{2-fluoro-3-[(3-furanylsulfonyl)amino]phenyl}-1,3-thiazol-2-yl)-1-piperidinecarboxylate(53 mg, 0.085 mmol) in ammonium hydroxide solution (28%, 2 mL, 51.4mmol) sealed in a 5-mL microwave tube was heated at 90° C. for 3 h underthe microwave conditions. The mixture was concentrated and dried underhigh vacuum to give 49 mg of the title compound. MS (ESI): 501.1 [M+1]⁺.

Step B:N-{3-[5-(2-amino-4-pyrimidinyl)-2-(4-piperidinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-3-furansulfonamide

To a solution of 1,1-dimethylethyl4-(5-(2-amino-4-pyrimidinyl)-4-{2-fluoro-3-[(3-furanylsulfonyl)amino]phenyl}-1,3-thiazol-2-yl)-1-piperidinecarboxylate(46 mg, 0.077 mmol) in dichloromethane (2 mL) was added TFA (0.5 mL,6.49 mmol), and the reaction mixture was stirred for 1 h. The reactionmixture was concentrated and the residue was purified using RP-HPLC. TheTFA salt was neutralized to give 22 mg of the title compound. MS (ESI):501.1 [M+1]⁺.

Example 325N-{3-[5-(2-amino-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]-2-chlorophenyl}-2,5-difluorobenzenesulfonamide

A suspension ofN-{2-Chloro-3-[5-(2-chloro-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]phenyl}-2,5-difluorobenzenesulfonamide(20 g, 34.3 mol) and saturated ammonium hydroxide (275 mL) was heated ina 1 L capacity Parr reactor @ 120° C. and 195-200 psi for 18 hrs. Themixture was cooled to ambient and the solid collected by filtration,washed with ethanol and dried to give ammonium salt of target compound(18.22 g). The mixture was suspended between ethyl acetate (1 L) andwater (0.5 L), pH of the stirring mixture adjusted carefully at 60° C.to ˜6.5 (first with 6N-HCl, then 1N-HCl) and the mixture filtered whilststill hot. The separated organic phase was washed with water, dried, andfiltered. The filtrate was concentrated under reduced pressure to about⅓ original volume during which time much solid crashed out; the paleyellow solid was filtered off, washed with more ethyl acetate and driedto give the title compound was obtained as a pale-yellow solid (12 g,21.2 mol, 62% yield). (400 MHz, DMSO-d₆) δ ppm 10.76 (br. s., 1H), 7.91(d, J=6.5 Hz, 1H), 7.60-7.40 (m, 5H), 7.47-7.52 (m, 3H), 7.39 (dd,J=5.8, 3.5 Hz, 1H), 6.56 (br. s, 2H), 5.60 (d, J=6.5 Hz, 1H), 3.68-3.77(m, 4H), 3.55 (d, J=4.3 Hz, 4H), MS (ESI): 565.0 [M+H]+.

Biological Examples

Compounds of the present invention were tested for B-Raf protein kinaseinhibitory activity in substrate phosphorylation assays and cellproliferation assays.

A. B-Raf Enzyme Assay:

Compounds of the present invention were tested for B-Raf protein serinekinase inhibitory activity in a B-Raf Accelerated MEK ATPase assay(BRAMA). Baculovirus-expressed His6-tagged BRAFV600E full-length (aminoacids 2-766) was used in the BRAMA assay. The BRAMA assay is a highsensitivity assay which measures an intrinsic MEK-mediated ATPhydrolysis uncoupled from downstream ERK phosphorylation by coupling theformation of ADP to NADH oxidation through the enzymes pyruvate kinaseand lactate dehydrogenase. When ADP production is initiated by additionof catalytic amounts of an activated Raf enzyme and non-phosphorylatedMEK, one observes robust ADP production concomitant with Raf-mediatedphosphorylation of MEK. The method is disclosed in: C. Rominger, M.Schaber, E. May. Assay for B-Raf Activity Based on Intrinsic MEK ATPaseActivity. Statutory Invention Registration Ser. No. 11/084,993 (March,2005) but includes the following changes: 1) the assay was performedwith a final MEK concentration of 150 nM and 2) the assay was read assingle end point instead of a kinetic read.

Acceleration of MEK ATPase activity was determined from the data andplotted as a function of inhibitor concentration to give concentrationresponse curves, from which the pIC50 values were generated followingstandard pIC50 fitting protocol.

Many of the exemplified compounds Examples 1-217 were run in the recitedassay (A). The results are reported in the following Table 1a in whichthe highest pIC50 for the one or more runs of each assayed compound iscategorized as indicated. In the following table:

-   “+” indicates no pIC50 measurement greater than 6 against B-Raf-   “++” indicates at least one pIC50 measurement greater than 6 against    B-Raf but no measurement greater than pIC50 of 7; and-   “+++” indicates at least one pIC50 measurement of greater than 7    against B-Raf.

TABLE 1a B-Raf Activity Example Activity 1 +++ 2 +++ 3 +++ 4 +++ 5 ++ 6+++ 7 ++ 8 +++ 9 ++ 10 +++ 11 +++ 12 +++ 13 +++ 14 +++ 15 +++ 16 +++ 17+++ 18 +++ 19 +++ 20 +++ 21 +++ 22 +++ 23 +++ 24 +++ 25 +++ 26 +++ 27+++ 28 +++ 29 +++ 30 +++ 31 +++ 32 +++ 33 +++ 34 +++ 35 +++ 36 ++ 37 ++38 ++ 39 +++ 40 +++ 41 +++ 42 +++ 43 +++ 44 +++ 45 +++ 46 +++ 47 +++ 48++ 49 ++ 50 ++ 51 + 52 ++ 53 +++ 54 +++ 55 ++ 56 +++ 57 +++ 58 +++ 59+++ 60 +++ 61 +++ 62 +++ 63 ++ 64 +++ 65 +++ 66 +++ 67 +++ 68 ++ 69 +++70 +++ 71 +++ 72 +++ 73 +++ 74 +++ 75 +++ 76 +++ 77 +++ 78 +++ 79 +++ 80+++ 81 +++ 82 +++ 83 +++ 84 ++ 85 ++ 86 +++ 87 +++ 88 +++ 89 +++ 90 +++91 +++ 92 +++ 93 +++ 94 +++ 95 +++ 96 +++ 97 +++ 98 +++ 99 +++ 100 +++101 +++ 102 +++ 103 +++ 104 +++ 105 +++ 106 +++ 107 +++ 108 NT 109 +++110 ++ 111 +++ 112 ++ 113 +++ 114 ++ 115 + 116 +++ 117 +++ 118 +++ 119++ 120 +++ 121 +++ 122 +++ 123 +++ 124 +++ 125 +++ 126 +++ 127 +++ 128+++ 129 +++ 130 +++ 131 +++ 132 +++ 133 ++ 134 +++ 135 +++ 136 +++ 137+++ 138 +++ 139 +++ 140 +++ 141 +++ 142 +++ 143 +++ 144 +++ 145 +++ 146+++ 147 +++ 148 +++ 149 +++ 150 ++ 151 +++ 152 +++ 153 +++ 154 +++ 155+++ 156 +++ 157 +++ 158 +++ 159 ++ 160 ++ 161 ++ 162 ++ 163 + 164 + 165++ 166 ++ 167 ++ 168 ++ 169 + 170 + 171 ++ 172 ++ 173 ++ 174 ++ 175 +++176 +++ 177 +++ 178 +++ 179 +++ 180 +++ 181 ++ 182 +++ 183 +++ 184 +++185 +++ 186 +++ 187 +++ 188 +++ 189 +++ 190 +++ 191 +++ 192 +++ 193 +++194 +++ 195 +++ 196 +++ 197 +++ 198 +++ 199 +++ 200 +++ 201 +++ 202 +++203 +++ 204 +++ 205 +++ 206 +++ 207 +++ 208 +++ 209 +++ 210 +++ 211 +++212 +++ 213 +++ 214 +++ 215 +++ 216 +++ 217 +++

At a time after the assay runs shown in Table 1a, above, many of theexemplified compounds Examples 1-217 were re-run and many of theexemplified compounds of Examples 218-325 were run one or more times inthe recited assay (A). The results are reported in the following Table1b in which the average pIC50 for the one or more runs of each assayedcompound is categorized as indicated. In the following table:

pIC50 values for the compounds of the examples were categorized byrelative inhibition of B-Raf. The results are summarized in the tablesbelow.

B-Raf pIC₅₀ Example no. 8.5 and over 1, 2, 11-15, 18, 20, 21, 24, 26,30-33, 40-43, 45, 54, 56, 57, 58a, 58d, 60, 61, 62, 64, 65, 66, 67, 69,72, 74, 75, 78, 79, 81, 83, 91, 96-99, 101, 103, 104, 105, 107, 117,118, 130, 132, 135, 137, 138, 142, 144, 154-157, 176, 177, 179, 182,185, 187-192, 194-199, 201, 203, 207-214, 217, 218, 221, 223, 224, 226,227, 228, 230, 231, 232, 233, 234, 236, 238, 240-245, 252, 256, 258-270,273, 280, 281, 290-307, 309, 312, 319, 320, 322, and 324 >7.5-<8.5 3, 8,10, 16, 17, 19, 22, 23, 25, 27, 28, 29, 34, 35, 39, 44, 46, 47, 53, 59,70, 71, 73, 76, 77, 80, 87, 88, 92, 93, 94, 100, 102, 106, 115, 116,120, 121, 125, 128, 129, 134, 136, 139, 140, 141, 143, 148, 151, 152,153, 180, 184, 186, 193, 200, 204, 205, 206, 215, 216, 219, 220, 222,225, 229, 235, 237, 239, 246-251, 253, 254, 255, 257, 271, 272, 274-279,283, 286, 287, 311, 313-315, 316, 321, and 323  6.0-7.5 4-7, 9, 36, 37,38, 48, 49, 50, 52, 55, 63, 68, 68, 84, 85, 86, 89, 90, 95, 109-114,119, 122, 123, 124, 126, 127, 131, 133, 145, 146, 147, 149, 150,158-162, 165-168, 175, 178, 181, 183, 202, 282, 284, 285, 288, 289, and310B. Cellular Assays—Cell Growth Inhibition Assay

Human colon tumor cells (Colo205) were cultured in RPMI (Mediatech50-020-PB) containing 10% FBS and 1% penicillin-streptomycin. Humanmelanoma cancer cells (SK-MEL-28) were cultured in EMEM withnonessential amino acids (Mediatech 50-011-PB) containing 10% FBS, 1%sodium pyruvate (JT Baker 3354-04), and 1% penicillin-streptomycin. Allcell lines were maintained at 37° C. in a humidified 5% CO₂, 95% airincubator. Cells were harvested using trypsin/EDTA (Invitrogen 25200),counted using a haemocytometer, and plated. For 96-well assays (usingwhite full-area NUNC plates cat. #136102), cells were plated in 105 μLat the following densities (cells/well): Colo205, 500; SK-MEL-28, 500.For 384-well assays (white full-area NUNC plates, cat. #781080), cellswere plated in 48 μL at the following densities (cells/well): Colo205,500; SK-MEL-28, 500.

The next day, compounds were diluted as follow: For 96-well assays, 13.5μL of compound in DMSO were diluted using nine (9) serial 1:3 dilutionsof 4.5 μL in 9 μL of DMSO. Medium (270 μL/well of RPMI with 10% FBS and1% penicillin-streptomycin) was added to the plates. Aliquots (7 μL)were added to cells in the final assay giving a final DMSO concentrationof 0.2%. For 384-well assays, 15 μL of compound in DMSO were dilutedusing nine (9) serial 1:3 dilutions of 5 μL in 10 μL of DMSO, followedby a further dilution of 5 μL of compound with 95 μL of medium, of which2 μL were added to cells in the final assay giving a final DMSOconcentration of 0.2%. Cells were incubated at 37° C., 5% CO₂ for 3days.

Total ATP was measured (as a surrogate estimate of cell number) usingCellTiter-Glo® reagent (Promega G7571). Briefly, plates were removedfrom the incubator and allowed to equilibrate to room temperature for 30minutes. CellTiter-Glo® (25 μL or 55 μL for 384-well or 96-well assays,respectively) reagent was added to each well and plates were shaken onan orbital plate shaker for 2 minutes. Plates were incubated withoutshaking for a further 30 minutes and read on an LJL Analyst GT reader inluminometer mode with an integration time of 0.5 seconds per well.Percent inhibition of cell growth was calculated relative to DMSOvehicle-treated control wells. Concentration of compound required togive 50% inhibition of vehicle-treated control cell growth (IC₅₀) wasinterpolated using a 4-parameter fit for determining IC₅₀ using thefollowing equation: Y=A+((B−A)/(1+((C/X)^D))) where X═IC₅₀.

Many of the compounds of Examples 1-217 were run in the recited assayand the results are reported in the following Table 2a. In the followingtable:

-   “+” indicates that the compound showed activity of >1 μM in Colo205    tumor cells;-   “++” indicates that the compound showed activity of between 100 nM    and 1 μM in Colo205 tumor cells; and-   “+++” indicates that the compound showed activity of less than 100    nM in Colo205 tumor cells.

TABLE 2a Activity in Colo205 Tumor Cells Example Activity 1 +++ 2 +++ 3+++ 4 ++ 5 ++ 6 + 7 + 8 ++ 9 + 10 +++ 11 +++ 12 +++ 13 +++ 14 +++ 15 +++16 +++ 17 +++ 18 +++ 19 +++ 20 +++ 21 ++ 22 +++ 23 ++ 24 +++ 25 ++ 26+++ 27 ++ 28 +++ 29 ++ 30 +++ 31 +++ 32 +++ 33 +++ 34 + 35 ++ 36 + 37 ++38 + 39 ++ 40 ++ 41 +++ 42 +++ 43 ++ 44 + 45 ++ 46 ++ 47 ++ 48 ++ 49 ++50 + 51 + 52 ++ 53 +++ 54 +++ 55 ++ 56 +++ 57 +++ 58 +++ 59 ++ 60 +++ 61++ 62 ++ 63 ++ 64 +++ 65 +++ 66 +++ 67 +++ 68 + 69 ++ 70 ++ 71 ++ 72 ++73 + 74 +++ 75 +++ 76 ++ 77 +++ 78 +++ 79 +++ 80 ++ 81 +++ 82 +++ 83 +++84 + 85 + 86 + 87 ++ 88 ++ 89 ++ 90 ++ 91 +++ 92 +++ 93 ++ 94 ++ 95 ++96 +++ 97 +++ 98 +++ 99 ++ 100 ++ 101 +++ 102 ++ 103 +++ 104 +++ 105 +++106 ++ 107 +++ 108 NT 109 + 110 NT 111 NT 112 NT 113 NT 114 NT 115 + 116+++ 117 +++ 118 ++ 119 + 120 ++ 121 ++ 122 + 123 ++ 124 ++ 125 ++ 126 ++127 + 128 + 129 ++ 130 +++ 131 + 132 ++ 133 + 134 ++ 135 ++ 136 ++ 137+++ 138 +++ 139 +++ 140 +++ 141 +++ 142 +++ 143 ++ 144 +++ 145 ++ 146 ++147 ++ 148 + 149 ++ 150 ++ 151 ++ 152 +++ 153 +++ 154 ++ 155 ++ 156 +++157 +++ 158 + 159 ++ 160 ++ 161 + 162 ++ 163 + 164 + 165 ++ 166 ++ 167++ 168 ++ 169 + 170 + 171 ++ 172 ++ 173 ++ 174 ++ 175 ++ 176 +++ 177 +++178 ++ 179 +++ 180 ++ 181 + 182 +++ 183 + 184 +++ 185 +++ 186 ++ 187 +++188 +++ 189 +++ 190 +++ 191 +++ 192 ++ 193 ++ 194 +++ 195 +++ 196 +++197 +++ 198 ++ 199 +++ 200 ++ 201 +++ 202 + 203 +++ 204 +++ 205 ++ 206+++ 207 +++ 208 +++ 209 +++ 210 +++ 211 +++ 212 +++ 213 +++ 214 +++ 215+++ 216 NT 217 NT

At a time after the assay runs shown in Table 2a, above, many of theexemplified compounds Examples 1-217 were re-run and many of theexemplified compounds of Examples 218-325 were run one or more times inthe recited assay (B). The results are reported in the following Table2b in which the average inhibition for the one or more runs of eachassayed compound is categorized as indicated. In the following table:

-   -   IC50 (nM) values for compounds of select examples were        categorized by relative inhibition of cell proliferation. The        results are summarized in the tables below.

IC50 for Colo205 Example No. <100 nM 1, 2, 3, 10-20, 22, 26, 28, 30, 31,32, 33, 41, 42, 53, 54, 56, 57, 58a, 58d, 60, 64, 65, 66, 67, 74, 75,77, 78, 79, 81, 83, 91, 92, 96-98, 101, 103, 104, 105, 107, 116, 117,130, 137, 138, 140, 141, 142, 144, 152, 153, 156, 157, 176, 179, 182,184, 185, 188, 189, 190, 191, 195, 196, 197, 199, 201, 203, 204,206-253, 255, 256, 258, 259, 262, 264, 266, 269, 281, and 295 100 nM to1000 nM 8, 21, 23, 24, 25, 27, 29, 35, 37, 39, 40, 43, 45-49, 52, 55,59, 61, 62, 63, 69-72, 76, 80, 97, 88, 89, 90, 93, 94, 95, 99, 100, 102,106, 113, 118, 120, 121, 123-126, 129, 132, 134, 135, 136, 139, 143,145, 146, 147, 149, 150, 151, 154, 155, 159, 160, 162, 165, 166, 167,168, 175, 178, 180, 186, 192, 193, 198, 200, 205, 254, 263, 267, 270,271, 272, 278, 280, and 282-287 >1000 nM-10 μM 4-7, 9, 34, 38, 44, 50,51, 68, 73, 84, 86, 109, 110, 111, 112, 115, 122, 127, 128, 133, 148,158, 161, 163, 164, 177, 181, 183, 187, and 202

Many of the compounds of Examples 1-217 were run in the recited assayand the results are reported in the following Table 3a. In the followingtable:

-   “+” indicates that the compound showed activity of >1 μM in    SK-MEL-28 tumor cells;-   “++” indicates that the compound showed activity of between 100 nM    and 1 μM in SK-MEL-28 tumor cells; and-   “+++” indicates that the compound showed activity of less than 100    nM in SK-MEL-28 tumor cells.

TABLE 3a Activity in SK-MEL-28 Tumor Cells Example Activity 1 +++ 2 +++3 +++ 4 ++ 5 ++ 6 + 7 + 8 ++ 9 + 10 +++ 11 +++ 12 +++ 13 +++ 14 +++ 15+++ 16 +++ 17 +++ 18 +++ 19 +++ 20 +++ 21 ++ 22 +++ 23 ++ 24 +++ 25 +++26 +++ 27 ++ 28 +++ 29 ++ 30 +++ 31 +++ 32 +++ 33 +++ 34 + 35 ++ 36 + 37++ 38 + 39 ++ 40 ++ 41 +++ 42 +++ 43 ++ 44 + 45 ++ 46 ++ 47 ++ 48 ++ 49++ 50 + 51 + 52 ++ 53 +++ 54 +++ 55 + 56 +++ 57 +++ 58 +++ 59 ++ 60 +++61 ++ 62 ++ 63 ++ 64 +++ 65 +++ 66 +++ 67 +++ 68 + 69 ++ 70 ++ 71 ++ 72+++ 73 + 74 ++ 75 +++ 76 ++ 77 +++ 78 +++ 79 +++ 80 ++ 81 +++ 82 +++ 83+++ 84 + 85 + 86 + 87 ++ 88 + 89 ++ 90 ++ 91 +++ 92 +++ 93 ++ 94 ++ 95++ 96 +++ 97 +++ 98 +++ 99 ++ 100 ++ 101 +++ 102 ++ 103 +++ 104 +++ 105+++ 106 ++ 107 +++ 108 NT 109 + 110 NT 111 NT 112 NT 113 NT 114 NT 115 +116 +++ 117 +++ 118 ++ 119 + 120 ++ 121 ++ 122 + 123 + 124 ++ 125 ++ 126++ 127 + 128 + 129 ++ 130 +++ 131 + 132 ++ 133 + 134 ++ 135 +++ 136 ++137 +++ 138 + 139 +++ 140 +++ 141 +++ 142 +++ 143 ++ 144 +++ 145 ++ 146++ 147 ++ 148 + 149 ++ 150 ++ 151 ++ 152 +++ 153 +++ 154 ++ 155 ++ 156+++ 157 +++ 158 + 159 ++ 160 ++ 161 + 162 ++ 163 + 164 + 165 ++ 166 ++167 + 168 ++ 169 + 170 + 171 ++ 172 ++ 173 + 174 ++ 175 ++ 176 +++ 177+++ 178 ++ 179 +++ 180 ++ 181 + 182 +++ 183 + 184 +++ 185 +++ 186 ++ 187+++ 188 +++ 189 +++ 190 +++ 191 +++ 192 ++ 193 ++ 194 +++ 195 +++ 196+++ 197 +++ 198 ++ 199 +++ 200 ++ 201 +++ 202 ++ 203 +++ 204 +++ 205 ++206 +++ 207 +++ 208 +++ 209 +++ 210 +++ 211 +++ 212 +++ 213 +++ 214 +++215 +++ 216 NT 217 NT

At a time after the assay runs shown in Table 3a, above, many of theexemplified compounds Examples 1-217 were re-run and many of theexemplified compounds of Examples 218-325 were run one or more times inthe recited assay (B). The results are reported in the following Table3b in which the average inhibition for the one or more runs of eachassayed compound is categorized as indicated. In the following table:

-   -   IC50 (nM) values for compounds of select examples were        categorized by relative inhibition of cell proliferation. The        results are summarized in the tables below.

IC50 for SK-MEL-28 Example No. <100 nM 1, 2, 3, 10-20, 22, 25, 26, 28,30, 31, 32, 33, 42, 53, 54, 56, 57, 58a, 58d, 60, 64, 65, 66, 67, 72,75, 77, 78, 79, 81, 83, 91, 92, 96, 97, 98, 101, 103, 104, 105, 107,116, 117, 130, 135, 137, 138, 140, 141, 142, 144, 152, 153, 156, 157,176, 179, 182, 184, 185, 187, 188, 189, 190, 191, 192, 194, 195, 196,197, 199, 201, 203, 204, 206-249, 251-256, 258, 259, 262, 264, 265, 266,271, 272, 281, and 295 100 nM to 1000 nM 4, 5, 8, 21, 23, 24, 27, 29,35, 37, 39, 40, 41, 43, 45, 46, 47, 48, 49, 52, 59, 61, 62, 63, 69, 70,71, 74, 76, 80, 87, 89, 90, 93, 94, 95, 99, 100, 102, 106, 113, 118,120, 121, 124, 125, 126, 129, 132, 134, 136, 139, 143, 145, 146, 147,149, 150, 151, 154, 155, 159, 160, 162, 165, 166, 168, 175, 178, 180,186, 193, 198, 200, 202, 205, 250, 263, 267, 269, 270, 278, 280, 283,284, 286, and 287 >1000 nM-10 μM 6, 7, 9, 34, 38, 44, 50, 51, 55, 68,73, 86, 88, 109, 110, 111, 115, 119, 122, 123, 127, 131, 133, 148, 158,161, 164, 167, 177, 181, 183, 282, and 285C. Mutant Cancer Cell Lines

Twenty two (22) cancer cell lines encoding B-Raf V600E mutation,cultured generally according to instructions supplied by cell culturesupplier American Type Culture Collection, Manassas, Va., were testedfor sensitivity to the compound of example 58a in a 3 day proliferationassay. Data demonstrated that 16 out of 22 cancer cell lines encodingB-Raf V600E were sensitive with gIC50<100 nM while 2 out of 22demonstrated an intermediate response (gIC50≧100 nM and <1000 nM) and 4out of 22 were not sensitive (gIC50>1000M) to the compound. Activity ofthe compound of example 58a against B-Raf V600E mutant cancer cell linesis shown in Table 4.

TABLE 4 Tissue Mean gIC₅₀ CELL LINE Origin BRAF (nM) MALME-3M Skin V600E(+++) UACC-62 Skin V600E (+++) C32TG Skin V600E (+++) SK-MEL-1 SkinV600E (+++) UCLA-SO-M14 Skin V600E (+++) SK-MEL-28 Skin V600E (+++)DU4475 Breast V600E (+++) WM115 Skin V600D, V600E (+++) UACC-257 SkinV600E (+++) COLO 205 Colon V600E (+++) SK-MEL-3 Skin V600E (+++) A375PF11s Skin V600E (+++) SH-4 Skin V600E (+++) A101D Skin V600E (+++) ES-2Ovary V600E (+++) HT-29 Colon T119S, V600E (+++) SW1417 Colon V600E (++)SW872 Connective tissue V600E (++) RKO Colon V600E (−) A673 Muscle V600E(−) GCT Skin V600E (−) NCI-H292 Lung T119S, V600E (−) (+++) gIC50 <100nM (++) gIC50 ≧100 nM and <1000 nM (−) gIC50 ≧1000 nMD. In Vivo Experiments

1. Dose Dependent Tumor Inhibition Using Compound of Example 58a

A375P F11s were cultured in RPMI 1640 medium supplemented with 10% fetalbovine serum, 1% Penicillin-streptomycin and 1% sodium pyruvate. Tumorcells (2×10⁶ A375P F11s) were implanted subcutaneously into the rightflank of athymic mice on Day 1. To facilitate their growth, A375P F11scells were suspended in Matrigel diluted 1:1 in phosphate-bufferedsaline before implantation. When tumors had reached approximately 200mm³ in volume (Day 19-22), tumor-bearing mice were randomized into studygroups (n=7 or 8). Animals were dosed orally once or twice daily for a14-day period. The compound of Example 58a was dosed in a 0.5% HPMC/0.2%Tween 80 pH 7-8 vehicle. Tumor growth was measured twice a week usingcalipers for the duration of the study. Tumor volumes were calculated asa product of (length×width×width)/2 and median values were used tocompare groups. Complete regressions (CR) were defined as threeconsecutive tumor measurements of ≦13.5 mm³. Partial regressions weredefined as three consecutive measurements of ≦50% of starting tumorvolume. Tumor growth delay was defined as the difference in time takenfor treated and control groups to reach 1000 mm³ (T-C1000).

In the following table:

-   -   “−” indicates no response    -   “+” indicates growth delay (1-2× doubling)    -   “++” indicates growth delay (>2× doubling)    -   “+++” indicates stable disease    -   “++++” indicates partial regression    -   “+++++” indicates complete regression

TABLE 5 In vivo Evaluation Tumor Line Dosage Response A375P F11s 300mg/kg bid ++++(+) A375P F11s 300 mg/kg qd ++++(+) A375P F11s 100 mg/kgbid ++++(+) A375P F11s 100 mg/kg qd ++++(+) A375P F11s 10 mg/kg qd ++(+)A375P F11s 1 mg/kg qd + A375P F11s 0.1 mg/kg qd −

2. Pharmacodynamic Effect of Various Compounds

Activity of select exemplified compounds was tested in vivo againstA375PF11s (melanoma cell line encoding a B-Raf V600E mutation) xenograftmouse model. The A375P F11s cell line, encoding a mutation forBRAF^(V600E), was subcloned from the A375P human melanoma cell line(obtained from ATCC, Cat # CRL-1619) by limiting dilution and selectedbased on high (90%) sensitivity to the BRAF inhibitor, SB-590885(commercially available), in 3-day proliferation assays. The selectedclone (A375P F11s) was isolated and mutation in B-Raf (T1799A) encodingthe V600E amino acid change was reconfirmed.

Female CD-1 nu/nu mice of 8-10 weeks in age were used in these studies;all mice were obtained from Charles River Laboratories (Wilmington,Del.). Animals were housed in pathogen free conditions and handled withaseptic technique. A375P F11s were harvested from culture flasks byexposure to 0.25% trypsin/EDTA for 5 min at 37° C. Detached cells werecollected, centrifuged (1500 rpm, 5 min, 4° C.) and rinsed to remove thetrypsin solution. Cells were resuspended in PBS without magnesium orcalcium and counted. Cells were spun as previously to remove PBS and asingle cell suspension was created either in 50% Matrigel: 50% PBS (v:v)or 100% PBS so that a 100 μL subcutaneous injection would deliver therequired number of cells per mouse. The A375P F11s melanoma line wasinjected with Matrigel at 4 million cells per mouse. Tumors wereestablished (˜150-300 mm³) for all cell lines within 2-4 weekspost-injection.

Compounds of examples 24, 25, 26, 57, 58, 59, 64, 65, 66, and 156 wereprepared in formulations of either 0.5% HPMC/0.2% TWEEN 80 ph 7-8 or 20%encapsin/1% DMSO. The preparations were administered orally to the miceas a single oral dose of 100 mg/kg.

At 2 h following oral administration of compound mice were euthanizedusing carbon dioxide. Tumors were carefully excised, homogenized usingMedimachine (BD Bioscience) with 1 ml of lysis buffer (25 mM Tris-HCl(pH 7.5), 2 mM EDTA (pH 8.0), 2 mM EGTA (pH 8.0), 1% Triton X-100, 0.1%SDS, 50 mM Na—B—PO4, 2 mM NaVO4, 4 mM Na-Pyr-PO4, 2× phosphataseinhibitor cocktail. Crude homogenate was transferred to a 12 mlpolypropylene tube containing 1.5 ml of lysis buffer and kept on ice.Following homogenization of all samples, 1 ml of homogenate wastransferred to an eppendorf tube and centrifuged at 14,000 rpm for 15min at 4° C. Five hundred microliter of clarified lysate was transferredto a new tube, flash frozen and processed for quantitation of pERK andtERK using western blot or Elisa (MSD) assays. Before the ratio ofpERK/tERK was determined and to ensure linear range, a BSA standardcurve was made by performing serial ⅓-fold dilution to reachconcentrations of 20, 13.3, 8.9, 5.9, 3.9, 2.6, 1.7, 1.2, 0.8, 0.5, 0μg/μl. BioRad dye was added to BSA dilutions and diluted test lysates.Samples were incubated at room temperature for 15 min and read on theSpectraMax plate reader at 595 nM. Comparison to the standard curveprovides a relative measurement of protein concentration. Fordetermination of pERK/tERK ratio by western blot analysis 50 μgmicrogram of tumor lysates were electrophoresed on Invitrogen 4-12%bis-Tris HCl SDS-PAGE. The gels were transferred onto nitro-cellulosemembranes using the iBlot transfer apparatus, which were then blockedand incubated with different primary antibodies overnight at 4° C.Western blots dually probed against pERK and tERK were scanned usingLI-COR Odyssey® reader. A ratio of the immunofluorescent densityobtained for pERK/tERK is calculated and expressed as a ratio (inpercentage) to control untreated samples. For determination of pERK/tERKratio by ELISA, MesoScale Discovery (MSD) (cat# K15107) plate were usedaccording to manufacturer's instructions. In brief, MSD plates wereblock with 150 μl/well of blocking buffer for 1 hr before being washed 4times with 200 μl of washing buffer. Thirty microliter (30 μl) ofserially diluted samples was added to wells and plates were incubatedovernight at 4° C. under slow agitation (˜500 rpm). Plates were washed 4times in 200 μl 1× Tris wash buffer and 25 μl detection antibodysolution was added to all wells and incubated at room temperature for 1hr (˜500 rpm). Plates were washed 4 times in 200 μl wash buffer and 1500of read buffer was added to all wells. Plates were read on MSD.SI6000.In this assay vehicle and compound treated samples were tested at 4different dilutions to allow linear range coverage of the assay. FrompERK and tERK signal, background (BSA signal) was subtracted and ratioof pERK/tERK determined and normalized to untreated vehicle samples,arbitrarily set at 100%.

Inhibition of pERK by B-Raf inhibitors is a good pharmacodynamic marker(PD marker) for BRAF inhibition. The compounds of examples 24, 25, 26,57, 58, 59, 64, 65, 66, and 156 exhibited inhibition of pERK (pERK/tERK)of equal to or greater than 30%.

3. Efficacy In Vivo Study in Mouse.

Of the 10 compounds tested for inhibition of pERK, in C.2 above, eightof the compounds (compounds described in example numbers 24, 26, 58, 59,64, 65, 66, and 156) were tested in an efficacy study similar to studyD.1 above. The results demonstrate that six of the eight testedcompounds caused tumor regression (mean tumor volume smaller after 14day treatment than initial tumor volume) or stable disease (mean tumorvolume similar after 14 day treatment to initial mean tumor volume)compared to vehicle treated animals.

Pharmaceutical Formulation Example—Preparation of Capsules Containing aCompound of the Invention (Freebase):

-   -   Contents in each capsule: =60 mg Active Pharmaceutical        ingredient (API)+60 mg Avicel+13 mg SSG.    -   133 mg total powder in a size 0 hard gelatin capsule. The        Avicel/SSG weight may be reasonably approximate.        Procedure:        1. Separate the halves of hard-gelatin capsule and mark/identify        each as appropriate/needed.        2. Place the bottom capsule half in capsule filler with the        filling funnel on top.        3. Weigh the components (Avicel, Sodium Starch Glycolate (SSG),        API) onto a single weigh paper (tared on an analytical balance        between each weighing).        4. Record weights of each component.        5. Carefully and thoroughly mix the dry powders on the weigh        paper with a small spatula.        6. Carefully transfer the mixed powders into the capsule through        the funnel.        7. Place the top half onto the capsule and close until secure,        shake capsule to mix/distribute contents.        8. IF powder begins to near top of capsule, gently tap capsule        and powder should settle.        9. Place the capsule into a small appropriately labeled bottle        (but large enough to easily remove it).        Pharmaceutical Formulation Example—Preparation of Tablets        Containing a Compound of the Invention (Freebase):

Quantity Component (mg/tablet) % w/w Core Tablet API 405.0 71.6 Lactosemonohydrate 59.0 10.4 Polysorbate 80 1.0 0.2 Povidone 40.0 7.1 ColloidalSilicon Dioxide 5.5 1.0 Crospovidone 51.0 9.0 Magnesium Stearate 4.5 0.8Purified Water qs Film Coating Opadry ® Orange, YS-1-13065-A 17.0 3.0Purified water qsProcedure:1. Sieve Lactose, Silicon dioxide, Crospovidone and half Povidone.2. Add API.3. Granulate in High Shear Granulator with granulating solutioncontaining dissolved Polysorbate 80 and other half of Povidone inPurified water.4. Mill using Comil 197, 0.375″ screen.5. Dry using Fluid Bed Dryer6. Mill using Comil 197, 0.075″ screen7. Add Crospofidone, magnesium stearate.8. Blend 5 minute9. Compress tablet10. Aqueous film coat tabletX-Ray Crystallography of Example Nos. 58, 64 and 65:

The X-ray powder diffraction pattern of Form 1 of Example Nos. 58, 64and 65 can be determined using conventional techniques and equipmentknown to those skilled in the art of analytical chemistry and physicalcharacterization. The diffraction patterns of FIGS. 1, 3 and 5 wereobtained with a PANalytical diffractometer system utilizing copper KX-radiation and equipped with automated divergent slits, nickel filter,and a real time multiple strip detector. The powder sample used togenerate the X-ray powder diffraction data was mounted on a silicon zerobackground plate. In FIGS. 1, 3 and 5, 2 theta angles in degrees(x-axis) is plotted against peak intensity (y-axis). The XRD pattern foreach form of Example No. 58, 64 and 65 is unique to the particular form;exhibiting a unique set of diffraction peaks which can be expressed in 2theta angles ( ), d-spacings (Å) and/or relative peak intensities.

Since some margin of error is possible in the assignment of 2 thetaangles and d-spacings, the preferred method of comparing XRD patterns inorder to identify a particular form of a sample is to overlay the XRDpattern of the unknown sample over the XRD pattern of a known form. Forexample, one skilled in the art can overlay an XRD pattern of an unknownsample of Example No. 58, obtained using the methods described herein,over FIG. 1 and, using expertise and knowledge in the art, readilydetermine whether the XRD pattern of the unknown sample is substantiallythe same as the XRD pattern of Form 1 of Example No. 58. If the XRDpattern is substantially the same as FIG. 1, the previously unknown formcan be readily and accurately identified as Form 1 of Example No. 58.The same method may be used to compare a sample of an unknown form ofExample Nos. 64 and 65 with FIGS. 3 and 5.

Although 2 theta angles or d-spacings are the primary method ofidentifying a particular crystalline form, it may be desirable to alsocompare relative peak intensities. As noted above, relative peakintensities may vary depending upon the specific diffractometer employedand the analyst's sample preparation technique. The peak intensities arereported as intensities relative to the peak intensity of the strongestpeak. The intensity units on the XRD are counts/sec. The absolutecounts=counts/time×count time=counts/sec×10 sec.

Differential Scanning Calorimetry of Form 1 of Example Nos. 58, 64 and65.

Differential scanning calorimetry was carried out on TA Instruments DSCQ100 DSC system. Heating rate of 10° C. per minute. Sample size 0.4-1.5mg. The thermograms are provided at FIGS. 2, 4, and 6, respectively.

As an additional aspects, the present invention provides a particularsolid state form, identified as “Form 1” ofN-{3-[5-(2-amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide;a particular solid state form identified as “Form 1” ofN-{3-[5-(2-amino-4-pyrimidinyl)-2-(tetrahydro-2H-pyran-4-yl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide;and a particular solid state form identified as “Form 1” ofN-{3-[2-(1,1-dimethylethyl)-5-(2-methyl-4-pyrimidinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide.

What is claimed is:
 1. A method for treating a susceptible neoplasmselected from melanoma and non-small cell lung cancer in a mammal inneed thereof comprising the steps of: (a) analyzing a sample from saidneoplasm to determine whether an activating mutation is present in thecoding sequence for B-Raf in cells of said neoplasm; (b) selecting amammal having said neoplasm with an activating mutation in the codingsequence for B-Raf; and (c) administering a therapeutically effectiveamount the compound of formula

or a pharmaceutically acceptable salt thereof to the mammal selected instep (b).
 2. The method of claim 1, wherein the activating mutationpresent in the coding sequence for BRAF results in a BRAF having anamino acid substitution selected from the group consisting of R462I,I463S, G464V, G464E, G466A, G466E, G466V, G469A, G469E, D594V, F595L,G596R, L597V, L597R, T599I, V600E, V600D, V600K, V600R, T119S, andK601E.
 3. The method of claim 2, wherein the activating mutation presentin the coding sequence for BRAF results in a BRAF having a V600E aminoacid substitution.
 4. The method of claim 1, wherein said neoplasm ismelanoma.
 5. The method of claim 4, wherein said neoplasm is metastaticmelanoma.
 6. The method of claim 1, wherein the activating mutationpresent in the coding sequence for BRAF results in the coding sequenceof BRAF having a substitution of T1799A.
 7. The method of claim 1,wherein said mammal is a human.